Ahead of print articles
MULTIDOMAIN INTERVENTION TRIAL FOR PREVENTING COGNITIVE DECLINE AMONG OLDER ADULTS WITH TYPE 2 DIABETES: J-MIND-DIABETES
T. Sugimoto, A. Araki, H. Fujita, K. Fujita, K. Honda, N. Inagaki, T. Ishida, J. Kato, M. Kishi, Y. Kishino, K. Kobayashi, K. Kouyama, Y. Kuroda, S. Kuwahata, N. Matsumoto, T. Murakami, H. Noma, J. Ogino, M. Ogura, M. Ohishi, H. Shimada, K. Sugimoto, T. Takenaka, Y. Tamura, H. Tokuda, K. Uchida, H. Umegaki, T. Sakurai, J-MIND-Diabetes study group
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BACKGROUND: No multidomain intervention trials have been designed for the prevention of cognitive decline in older adults with type 2 diabetes.
OBJECTIVES: To investigate the efficacy of a multidomain intervention in preventing cognitive decline in older adults with type 2 diabetes and cognitive impairment.
DESIGN: Eighteen-month, multi-centered, randomized controlled trial.
SETTING: Twelve hospitals in Japan.
PARTICIPANTS: Outpatients with type 2 diabetes aged 70–85 years with cognitive impairment.
INTERVENTION: The multidomain intervention program includes management of metabolic and vascular risk factors, exercise, nutritional counseling, and promotion of social participation. Participants in the control group received usual care and treatment for type 2 diabetes.
MEASUREMENTS: The primary outcome was the change in a composite score combining several neuropsychological tests from baseline to the 18-month follow-up. To assess the differences in cognitive changes between the intervention and control groups, a mixed-effects model for repeated measures was used.
RESULTS: Between March 13, 2019, and May 8, 2020, 361 participants were screened, and 154 were randomly assigned to either the intervention group (n = 81) or the control group (n = 73). Finally, 110 participants completed the trial. The between-group difference in the composite score changes was 0.068 (95% confidence interval, −0.091 to 0.226). Analyses for secondary outcomes indicated a positive impact of the intervention on memory and indicated that the intervention led to changes in dietary habits with increased intakes of niacin and meat, along with weight reduction compared to the control group.
CONCLUSION: The multidomain intervention did not demonstrate efficacy in preventing cognitive decline. However, this trial provided proof-of-concept evidence that multidomain interventions may offer cognitive benefits and contribute to changes in dietary behavior and weight reduction in older adults with type 2 diabetes and cognitive impairment. These findings should be confirmed in future studies.
CITATION:
T. Sugimoto ; A. Araki ; H. Fujita ; K. Fujita ; K. Honda ; N. Inagaki ; T. Ishida ; J. Kato ; M. Kishi ; Y. Kishino ; K. Kobayashi ; K. Kouyama ; Y. Kuroda ; S. Kuwahata ; N. Matsumoto ; T. Murakami ; H. Noma ; J. Ogino ; M. Ogura ; M. Ohishi ; H. Shimada ; K. Sugimoto ; T. Takenaka ; Y. Tamura ; H. Tokuda ; K. Uchida ; H. Umegaki ; T. Sakurai ; J-MIND-Diabetes study group ; (2024): Multidomain Intervention Trial for Preventing Cognitive Decline among Older Adults with Type 2 Diabetes: J-MIND-Diabetes. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.117
CORRELATES OF SUBJECTIVE COGNITIVE DECLINE IN BLACK AMERICAN MEN
D.K. Esiaka, C. Nwakasi, A.Q. Briggs, D.F. Conserve, R.J. Thorpe Jr
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BACKGROUND: Past research suggests that subjective cognitive decline serves as an early and potentially important indicator that individuals may be at risk for future cognitive decline or neurodegenerative conditions. However, there is a dearth of studies on factors influencing the experience of subjective cognitive decline in Black Americans, especially in Black American men.
OBJECTIVE: The current study explored correlates of subjective cognitive decline in Black American men.
PARTICIPANTS: A total of 117 Black American men, with a mean age of 38.5 (SD = 7.14) years, participated in the study.
MEASUREMENT: Participants completed a survey that assessed their demographic characteristics, self-rated health, neighborhood problems, length of residency in neighborhood, bodily symptoms, sleep comorbidities, sleep difficulties, and subjective cognitive decline. Linear regression analyses was performed and standardized beta coefficients were reported to describe the estimated independent effect of the predictor variables.
RESULTS: We found that socioecomic status (β = -.222, p=.003), bodily symptoms (β = .246, p=.005), length of residency in neighborhood (β = .157, p=.029), and sleep difficulties (β = .305, p<.001) were significant correlates of subjective cognitive decline among Black American men.
CONCLUSION: These findings underscore the intricate roles of socioeconomic status, bodily symptoms, neighborhood factors, and sleep health in shaping subjective cognitive experiences in this population. Research on subjective cognitive decline can contribute to the early identification of individuals at risk for cognitive decline, allowing for timely interventions, lifestyle modifications, and potential preventive measures.
CITATION:
D.K. Esiaka ; C. Nwakas ; A.Q. Briggs ; D.F. Conserve ; R.J. Thorpe Jr (2024): Correlates of Subjective Cognitive Decline in Black American Men. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.162
NO ASSOCIATION FOUND: ADVERSE CHILDHOOD EXPERIENCES AND COGNITIVE IMPAIRMENT IN OLDER AUSTRALIAN ADULTS
J. Lian, K.M. Kiely, B.L. Callaghan, R. Eramudugolla, M. Mortby, K.J. Anstey
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OBJECTIVE: This study aimed to investigate the relationship between childhood adversity and cognitive impairment in older adults.
METHODS: We analysed data from 1568 participants aged 72-79 (M = 75.1, SD = 1.5, % male = 52.6%) from Wave 4 of the Personality and Total Health (PATH) Through Life Project. The outcome variable was the presence of mild cognitive impairment (MCI) or dementia, determined through a clinically validated algorithmic diagnostic criteria. Childhood adversity was assessed using a 17-item scale covering various domestic adversities such as poverty, neglect, physical abuse, and verbal abuse. Adversity was operationalised using cumulative analysis, dichotomisation (<3 adversities; 3+ adversities), and latent class analysis. Multiple logistic regressions were employed to estimate the association between childhood adversity and cognitive impairment, while controlling for covariates including education, gender, ethnicity, and APOE ε4 status.
RESULTS: Our analyses revealed no significant association between childhood adversity and the presence of MCI or dementia across all tested models. Sensitivity analyses, exploring alternative scenarios, consistently failed to yield statistically significant findings.
CONCLUSION: In contrast to prevailing research findings, this study does not support a link between childhood domestic adversity and late-life cognitive outcomes. These results underscore the mixed results on adversity and cognition, highlighting the need for further research. Future investigations should consider the roles of potential mediating and protective factors within this complex relationship.
CITATION:
J. Lian ; K.M. Kiely ; B.L. Callaghan ; R. Eramudugolla ; M. Mortby ; K.J. Anstey (2024): No Association Found: Adverse Childhood Experiences and Cognitive Impairment in Older Australian Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.133
DEVELOPMENT AND CONCURRENT VALIDITY OF THE SHORTFORM COGDRISK DEMENTIA RISK ASSESSMENT TOOL
K.J. Anstey, M.H. Huque, S. Kootar, R. Eramudugolla, M. Li
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Evidence-based dementia risk assessment is required to inform individual and policy-level dementia risk reduction interventions. We developed the CogDrisk Short Form (CogDrisk-SF) to assess dementia risk factors, for situations where time and resources are limited. To evaluate concurrent validity with the original CogDrisk, we conducted an online survey using a repeated-measures, counterbalanced design. Community dwelling participants (n = 647, 50.1% were female, mean age 62.2 years, age range 40-89) completed the survey. The mean(sd) score for CogDrisk-SF and the CogDrisk was 9.7 (5.3) and 9.9 (5.5), respectively. The intraclass correlation between the risk score obtained from CogDrisk and CogDrisk-SF was 0.92. Fish intake, insomnia and depression had percentage agreements of 79%, 87% and 89% respectively. Other items had >95% agreement except for loneliness (94%), hypertension (94%), cholesterol (93%), atrial fibrillation (91%) and cognitive activity (90%). Very high agreement between the CogDrisk-SF and original CogDrisk shows that CogDrisk-SF is valid for use in research and clinical practice.
CITATION:
K.J. Anstey ; M.H. Huque ; S. Kootar ; R. Eramudugolla ; M. Li (2024): Development and Concurrent Validity of the Short-Form CogDrisk Dementia Risk Assessment Tool. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.108
PERFORMANCE OF A SHORT VERSION OF THE EVERYDAY COGNITION SCALE (ECOG-12) TO DETECT COGNITIVE IMPAIRMENT
M. Manjavong, A. Diaz, M.T. Ashford, A. Aaronson, M.J. Miller, J.M. Kang, S. Mackin, R. Tank, B. Landavazo, D. Truran, S.T. Farias, M. Weiner, R. Nosheny, for the Alzheimer’s Disease Neuroimaging Initiative
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BACKGROUND: The Everyday Cognition (ECog) 12-item scale, a functional decline measurement, can distinguish dementia from cognitively unimpaired (CU). Limited data compare ECog-12 performance by raters (self vs. informant) and scoring systems (average numeric vs. categorical grouping) to differentiate cognitive statuses.
OBJECTIVES: To evaluate the performance of ECog-12 in differentiation cognitive statuses.
DESIGN: A cross-sectional diagnostic test study.
SETTING AND PARTICIPANTS: Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study are analyzed. Participants were aged 55-90 years old divided into subgroups based on diagnostic criteria.
MEASUREMENTS: We evaluated ECog-12 performance across different diagnostic groups, such as CU vs cognitive impairment (CI; mild cognitive impairment (MCI), and dementia), and the association between ECog-12 and CI. This procedure was repeated for self- and partner (informant)-reports. Additionally, types of ECog scores were also assessed, where an average ECog score was calculated (continuous numeric) as well as a categorical grouping (“any occasional declined” or “any consistently declined”) based on item-level responses to ECog questions.
RESULTS: ECog-12 cut-off scores of 1.36 (self-reported) and 1.45 (partner-reported) distinguish CU from CI with AUC 0.7 and 0.78, respectively. Adding a memory-concern question improved self-reported-ECog AUC to 0.79. Self- and partner-reported “consistently-declined” ECog-12 categorical grouping provided AUC 0.69 and 0.78. The study partner reported ECog-12 showed a greater association with CI than self-reported, with odds ratios of 35.45 and 8.79, respectively.
CONCLUSION: Study partner-reported ECog scores performed better than self-reported ECog-12 in differentiating cognitive statuses, and a higher study partner reported ECog score was a higher prognostic risk for CI. A memory concern question could enhance self-reported ECog-12 performance. This further emphasizes the need to obtain data from study partners for research and clinical practice.
CITATION:
M. Manjavong ; A. Diaz ; M.T. Ashford ; A. Aaronson ; M.J. Miller ; J.M. Kang ; S. Mackin ; R. Tank ; B. Landavazo ; D. Truran ; S.T. Farias ; M. Weiner ; R. Nosheny ; for the Alzheimer’s Disease Neuroimaging Initiative ; (2024): Performance of a Short Version of the Everyday Cognition Scale (ECog-12) to Detect Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.109
EVALUATING CAUSAL EFFECTS OF GUT MICROBIOME ON ALZHEIMER’S DISEASE
Q. Zhao, A. Baranova, H. Cao, F. Zhang
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BACKGROUND: The preceding evidence indicates a close correlation between imbalances in the gut microbiome and Alzheimer’s disease (AD), yet the direct causal relationship remains unclear. Our objective is to investigate this potential causal connection.
METHODS: We obtained summary results from two significant genome-wide association studies (GWAS) on gut microbiota (the MibioGen consortium and the Dutch Microbiome Project), along with one GWAS summary result for AD. Using a two-sample Mendelian randomization (TSMR) analysis, we examined the potential causal effects of gut microbiota on AD.
RESULTS: Our TSMR analysis revealed that 16 gut bacterial taxa were linked to a reduced risk of AD. These included phylum Tenericutes, classes Bacilli and Clostridia along with its order Clostridiales, family Bacteroidaceae, genus Bacteroides, and species Bifidobacterium bifidum (OR: 0.867~0.971, P ≤ 0.045). Conversely, the presence of 12 taxa correlated with an increased risk of AD. These comprised class Actinobacteria and its family Coriobacteriaceae, as well as class Betaproteobacteria, its order Burkholderiales, and its family Sutterellaceae (OR: 1.042~1.140, P ≤ 0.035).
CONCLUSION: Our research uncovered evidence suggesting certain gut bacterial species might play a causal role in AD risk, providing a fresh angle for AD treatment strategies.
CITATION:
Q. Zhao ; A. Baranova ; H. Cao ; F. Zhang ; (2024): Evaluating Causal Effects of Gut Microbiome on Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.113
INDEPENDENT AND JOINT ASSOCIATIONS OF SOCIOECONOMIC STATUS AND LIFESTYLE BEHAVIORS WITH COGNITIVE IMPAIRMENT AMONG ELDERLY CHINESE POPULATION
Y. Feng, S. Jia, W. Zhao, X. Wu, Y. Zuo, S. Wang, L. Zhao, M. Ma, X. Guo, C.S. Tarimo, Y. Miao, J. Wu
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BACKGROUND: Numerous studies have shown that there are socioeconomic disparities in people’s health. Health behavior is considered to be an effective strategy to alleviate socio-economic differences. However, the independent or joint relationship between socioeconomic status (SES) and lifestyle behaviors (LBs) on the cognition of Chinese elderly are not clear. Therefore, this study aimed to reveal the impact of SES and LBs on cognitive impairment in elder Chinese.
METHODS: The data from the 2017-2018 wave of Chinese Longitudinal Healthy Longevity Survey was used. SES was created using latent class analysis based on annual per-capita household income, education level, and occupation. Six LBs were considered in calculating LB scores. Restricted cubic splines were used to model the association of LB scores and cognitive impairment to investigate the dose-response relationship. LB scores were divided into three groups: unhealthy, intermediate, and healthy lifestyle. Multivariate Logistic regression models were applied to explore both the independent and joint effects of SES and LB scores on cognitive impairment.
RESULTS: Among 10,116 participants, 1,872 (18.51%) were recorded as having cognitive impariment. After adjusting for multivariable confounding factors, compared with participants of high SES, those of low SES had higher risks of cognitive impairment [Odds ratio (OR): 1.385; 95% confidence interval (CI): 1.137-1.689]. In contrast to those with unhealthy lifestyle, participants adhering to a healthy lifestyle were found to be associated with a reduced risk of cognitive impairment (OR: 0.198; 95%CI: 0.150-0.263). A non-linear relationship was observed between LB scores and cognitive impairment (Pnonlinearity =0.001), indicating a protective effect on cognitive impairment when having more than two LBs. Participants with high SES and engaged in healthy lifestyle had the lowest risk of cognitive impairment compared to those with low SES and unhealthy lifestyle (OR: 0.123; 95% CI 0.073-0.207).
CONCLUSION: Cognitive impairment has socioeconomic disparities among the elderly Chinese population. A healthy lifestyle may attenuate the impact of socioeconomic inequality on cognitive impairment, emphasizing the important role of LBs modification in reducing the disease burden of cognitive impairment, especially in the elderly population with low SES.
CITATION:
Y. Feng ; S. Jia ; W. Zhao ; X. Wu ; Y. Zuo ; S. Wang ; L. Zhao ; M. Ma ; X. Guo ; C.S. Tarimo ; Y. Miao ; J. Wu ; (2024): Independent and Joint Associations of Socioeconomic Status and Lifestyle behaviors with Cognitive Impairment among Elderly Chinese Population. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.127
BLOOD CATHEPSINS ON THE RISK OF ALZHEIMER’S DISEASE AND RELATED PATHOLOGICAL BIOMARKERS: RESULTS FROM OBSERVATIONAL COHORT AND MENDELIAN RANDOMIZATION STUDY
X.-H. Qian, G.-Y. Ding, S.-Y. Chen, X.-L. Liu, M. Zhang, H.-D. Tang
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BACKGROUND: Alzheimer’s disease (AD), the main type of dementia, involves in complex pathophysiological processes, including abnormal lysosomes function. Cathepsins are the predominant proteases responsible for the degradation of diverse substrates in the endo-lysosomal system. However, there was still a lack of systematic study on the causal association between cathepsins and AD.
METHODS: This study utilized Mendelian randomization (MR) to investigate the association between blood cathepsins and the risk of AD, as well as the level of amyloid-β (Aβ) and p-Tau in cerebrospinal fluid. Furthermore, an independent dataset was employed to corroborate the above result. Importantly, this study incorporated the Alzheimer’s disease Immunization and Microbiota Initiative study Cohort to further validate the alteration of blood cathepsins expression level and examine its correlation with cognitive level and plasma AD-related pathological markers.
RESULTS: Using MR method, we observed that high level of cathepsin L (CTSL) was associated with a lower risk of AD in both training and validation data. In observational cohort, we found there was decreased blood CTSL expression level in Aβ+ cognitive impaired (CI) group, compared with Aβ- cognitive unimpaired (CU) group. Correlation analysis revealed that blood CTSL expression level was negatively correlated with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) score, plasma Aβ42 and Aβ42/40 level in Aβ+ CI group. Mediation analysis showed that plasma Aβ42/40 level was the key mediator in the association between blood CTSL and MMSE score in Aβ+ CI participants.
CONCLUSION: This study revealed that blood CTSL was an important factor affecting the risk of AD, and it affected the cognitive level of AD patients through plasma Aβ42/40 level.
CITATION:
X.-H. Qian ; G.-Y. Ding ; S.-Y. Chen ; X.-L. Liu ; M. Zhang ; H.-D. Tang (2024): Blood Cathepsins on the Risk of Alzheimer’s Disease and Related Pathological Biomarkers: Results from Observational Cohort and Mendelian Randomization Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.107
A PILOT STUDY OF BRAIN BOOTCAMP, A LOW-INTENSITY INTERVENTION ON DIET, EXERCISE, COGNITIVE ACTIVITY, AND SOCIAL INTERACTION TO IMPROVE OLDER ADULTS’ DEMENTIA RISK SCORES
J. Siette, L. Dodds, K. Deckers, S. Köhler, I. Heger, P. Strutt, C. Johnco, V. Wuthrich, C.J. Armitage
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BACKGROUND: Little is known about the impact of short, low-intensity multidomain dementia risk reduction interventions in older adults.
OBJECTIVES: To examine the effectiveness and feasibility of a low-intensity multidomain lifestyle intervention on dementia risk and dementia literacy in Australian older adults.
DESIGN: Single-group pre-post design.
SETTING: Community-dwelling.
PARTICIPANTS: A total of 853 older Australians (Mean age=73.3 years, SD=6.1) recruited from the community.
INTERVENTION: A 3-month dementia risk reduction program, BRAIN BOOTCAMP, including education, personalised risk information, physical cues for healthier choices and goal setting and planning to target four modifiable risk factors of diet, exercise, cognitive activity and social interaction in older adults.
MEASUREMENTS: The ‘LIfestyle for BRAin health’ (LIBRA) index was used to assess participants’ modifiable dementia risk based on 12 factors, with higher scores indicating greater risk. Dementia literacy was measured using a modified questionnaire derived from Dutch and British surveys, encompassing knowledge, risk reduction, and awareness aspects. Paired t-tests were used to compare dementia risk scores and dementia literacy before and after the program. Multivariate regressions were performed to identify sociodemographic and psychological factors associated with change in the LIBRA index.
RESULTS: Program attrition was high (58.3%). Participants who completed the program had decreased dementia risk scores (Cohen’s d=0.59, p<0.001), increased dementia literacy and awareness (Cohen’s d=0.64, p<0.001) and increased motivation to change lifestyle behaviors (Cohen’s d=0.25-0.52, p<0.016). Participants with higher motivational beliefs had greater dementia risk reduction.
CONCLUSIONS: Improving older adults’ motivation and knowledge may help modify lifestyle behaviors to reduce dementia risk. However, program attrition remains a challenge, suggesting the need for strategies to enhance participant engagement and retention in such interventions.
CITATION:
J. Siette ; L. Dodds ; K. Deckers ; S. Köhler ; I. Heger ; P. Strutt ; C. Johnco ; V. Wuthrich ; C.J. Armitage (2024): A Pilot Study of BRAIN BOOTCAMP, a Low-Intensity Intervention on Diet, Exercise, Cognitive Activity, and Social Interaction to Improve Older Adults’ Dementia Risk Scores. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.104
POTENTIALLY MODIFIABLE DEMENTIA RISK FACTORS IN CANADA: AN ANALYSIS OF CANADIAN LONGITUDINAL STUDY ON AGING WITH A MULTI-COUNTRY COMPARISON
S. Son, M. Speechley, G.Y. Zou, M. Kivipelto, F. Mangialasche, H.H. Feldman, H. Chertkow, S. Belleville, H. Nygaard, V. Hachinski, F. Pieruccini-Faria, M. Montero-Odasso
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BACKGROUND: It has been suggested that up to 40% of dementia cases worldwide are associated with modifiable risk factors; however, these estimates are not known in Canada. Furthermore, sleep disturbances, an emerging factor, has not been incorporated into the life-course model of dementia prevention.
OBJECTIVE: To estimate the population impact of 12 modifiable risk factors in Canadian adults including sleep disturbances, by sex and age groups, and to compare with other countries.
DESIGN: Cross-sectional analysis of Canadian Longitudinal Study on Aging baseline data.
SETTING: Community.
PARTICIPANTS: 30,097 adults aged 45 years and older.
MEASUREMMENTS: Prevalence and Population Attributable Fractions (PAFs) associated with less education, hearing loss, traumatic brain injury, hypertension, excessive alcohol, obesity, smoking, depression, social isolation, physical inactivity, diabetes, and sleep disturbances.
RESULTS: The risk factors with the largest PAF were later life physical inactivity (10.2%; 95% CI, 6.8% to 13%), midlife hearing loss (6.5%; 3.7% to 9.3%), midlife obesity (6.4%; 4.1% to 7.7%), and midlife hypertension (6.2%; 2.7% to 9.3%). The PAF of later life sleep disturbances was 3.0% (95% CI, 1.8% to 3.8%). The 12 risk factors accounted for 51.9% (32.2% to 68.0%) of dementia among men and 52.4% (32.5% to 68.7%) among women. Overall, the combined PAF of all risk factors was 49.2% (31.1% to 64.9%), and it increased with age.
CONCLUSION: Nearly up to 50% of dementia cases in Canada are attributable to 12 modifiable risk factors across the lifespan. Canadian risk reduction strategies should prioritize targeting physical inactivity, hearing loss, obesity, and hypertension.
CITATION:
S. Son ; M. Speechley ; G.Y. Zou ; M. Kivipelto ; F. Mangialasche ; H.H. Feldman ; H. Chertkow ; S. Belleville ; H. Nygaard ; V. Hachinski ; F. Pieruccini-Faria ; M. Montero-Odasso (2024): Potentially Modifiable Dementia Risk Factors in Canada: An Analysis of Canadian Longitudinal Study on Aging with a Multi-Country Comparison. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.105
DIGITAL HEALTH TECHNOLOGIES FOR ALZHEIMER’S DISEASE AND RELATED DEMENTIAS: INITIAL RESULTS FROM A LANDSCAPE ANALYSIS AND COMMUNITY COLLABORATIVE EFFORT
S.A. Lott, E. Streel, S.L. Bachman, K. Bode, J. Dyer, C. Fitzer-Attas, J.C. Goldsack, A. Hake, A. Jannati, R.S. Fuertes, P. Fromy
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Digital health technologies offer valuable advantages to dementia researchers and clinicians as screening tools, diagnostic aids, and monitoring instruments. To support the use and advancement of these resources, a comprehensive overview of the current technological landscape is essential. A multi-stakeholder working group, convened by the Digital Medicine Society (DiMe), conducted a landscape review to identify digital health technologies for Alzheimer’s disease and related dementia populations. We searched studies indexed in PubMed, Embase, and APA PsycInfo to identify manuscripts published between May 2003 to May 2023 reporting analytical validation, clinical validation, or usability/feasibility results for relevant digital health technologies. Additional technologies were identified through community outreach. We collated peer-reviewed manuscripts, poster presentations, or regulatory documents for 106 different technologies for Alzheimer’s disease and related dementia assessment covering diverse populations such as Lewy Body, vascular dementias, frontotemporal dementias, and all severities of Alzheimer’s disease. Wearable sensors represent 32% of included technologies, non-wearables 61%, and technologies with components of both account for the remaining 7%. Neurocognition is the most prevalent concept of interest, followed by physical activity and sleep. Clinical validation is reported in 69% of evidence, analytical validation in 34%, and usability/feasibility in 20% (not mutually exclusive). These findings provide clinicians and researchers a landscape overview describing the range of technologies for assessing Alzheimer’s disease and related dementias. A living library of technologies is presented for the clinical and research communities which will keep findings up-to-date as the field develops.
CITATION:
S.A. Lott ; E. Streel ; S.L. Bachman ; K. Bode ; J. Dyer ; C. Fitzer-Attas ; J.C. Goldsack ; A. Hake ; A. Jannati ; R.S. Fuertes ; P. Fromy (2024): Digital Health Technologies for Alzheimer’s Disease and Related Dementias: Initial Results from a Landscape Analysis and Community Collaborative Effort. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.103
CONTINUOUS ASSOCIATIONS BETWEEN REMOTE SELFADMINISTERED COGNITIVE MEASURES AND IMAGING BIOMARKERS OF ALZHEIMER’S DISEASE
E.A. Boots, R.D. Frank, W.Z. Fan, T.J. Christianson, W.K. Kremers, J.L. Stricker, M.M. Machulda, J.A. Fields, J. Hassenstab, J. Graff-Radford, P. Vemuri, C.R. Jack, D.S. Knopman, R.C. Petersen, N.H. Stricker
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BACKGROUND: Easily accessible and self-administered cognitive assessments that can aid early detection for Alzheimer’s disease (AD) dementia risk are critical for timely intervention.
OBJECTIVES/DESIGN: This cross-sectional study investigated continuous associations between Mayo Test Drive (MTD) – a remote, self-administered, multi-device compatible, web-based cognitive assessment – and AD-related imaging biomarkers.
PARTICIPANTS/SETTING: 684 adults from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer’s Disease Research Center participated (age=70.4±11.2, 49.7% female). Participants were predominantly cognitively unimpaired (CU; 94.0%).
MEASUREMENTS: Participants completed (1) brain amyloid and tau PET scans and MRI scans for hippocampal volume (HV) and white matter hyperintensities (WMH); (2) MTD remotely, consisting of the Stricker Learning Span and Symbols Test which combine into an MTD composite; and (3) in-person neuropsychological assessment including measures to obtain Mayo Preclinical Alzheimer’s disease Cognitive Composite (Mayo-PACC) and Global-z. Multiple regressions adjusted for age, sex, and education queried associations between imaging biomarkers and scores from remote and in-person cognitive measures.
RESULTS: Lower performances on MTD were associated with greater amyloid, entorhinal tau, and global tau PET burden, lower HV, and higher WMH. Mayo-PACC and Global-z were associated with all imaging biomarkers except global tau PET burden. MCI/Dementia participants showed lower performance on all MTD measures compared to CU with large effect sizes (Hedge’s g’s=1.65-2.02), with similar findings for CU versus MCI only (Hedge’s g’s=1.46-1.83).
CONCLUSION: MTD is associated with continuous measures of AD-related imaging biomarkers, demonstrating ability to detect subtle cognitive change using a brief, remote assessment in predominantly CU individuals and criterion validity for MTD.
CITATION:
E.A. Boots ; R.D. Frank ; W.Z. Fan ; T.J. Christianson ; W.K. Kremers ; J.L. Stricker ; M.M. Machulda ; J.A. Fields ; J. Hassenstab ; J. Graff-Radford ; P. Vemuri ; C.R. Jack ; D.S. Knopman ; R.C. Petersen ; N.H. Stricker (2024): Continuous Associations between Remote Self-Administered Cognitive Measures and Imaging Biomarkers of Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.99
VALIDATION OF A COMMUNITY-BASED APPROACH TOWARD PERSONALIZED DEMENTIA RISK REDUCTION: THE KIMEL FAMILY CENTRE FOR BRAIN HEALTH AND WELLNESS
N.D. Anderson, D. D’Amico, S. Rotenberg, D.R. Addis, J. Gillen, D. Moore, J.A. Furlano, B. Tan, M. Binns, M. Santarossa, H. Chertkow, for the Canadian Consortium on Neurodegeneration in Aging (CCNA) CAN-THUMBS UP Study Group
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BACKGROUND/OBJECTIVES: The Kimel Family Centre for Brain Health and Wellness is a research-driven community centre testing the efficacy of personalized dementia risk reduction programming on dementia risk and cognition. The objective of this protocol is to validate this approach by following people for two years.
DESIGN/SETTING: Participants will receive a comprehensive dementia risk assessment, including nonmodifiable and modifiable risk factors, from which they will receive a Personalized Dementia Risk Report and Program Strategy, indicating their health conditions increasing and their risk level in five modifiable risk domains: physical activity, brain-healthy eating, cognitive engagement, social connections, and mental wellbeing. Equipped with this information, participants will enroll in programs within the Centre to address their risk factors. Changes to their dementia risk, cognition, and Personalized Program Strategy will be communicated through re-assessments of risk factors every six months (risk and cognition) and every year (comprehensive assessment).
PARTICIPANTS: Participants (n = 450) will be 50 years of age or older, without a diagnosis of dementia, and sufficiently fluent in English to complete the assessments and understand program instructors. One goal is that our participant sample will include people of low income (with fundraising providing free community centre membership), and from various ethno-racial backgrounds.
INTERVENTION: Participants will select programs to meet their Personalized Program Strategy. For physical activity, they will gradually work toward the Canadian Society for Exercise Physiology guidelines. For brain-healthy eating, they will learn about the Brain Health Food Guide and food label reading, and then take additional programs. For cognitive engagement and mental wellbeing, they will take at least one hour of relevant programming per week. Social connections will be reinforced throughout all programs. All participants will also have access to the Canadian Consortium on Neurodegeneration’s CAN-THUMBS Up online, educational program on modifiable dementia risk factors, called Brain Health PRO.
MEASUREMENTS: The comprehensive assessment includes numerous dementia risk factors, but the primary measures are risk in the five domains, health conditions proximal to those five risk domains, and cognition, and how these are affected by adherence and quality of goal-directed future simulation. We hypothesize a reduced risk in the five domains within six months, improvements in health biomarkers within a year, and maintenance of cognition within two years, with these benefits accruing with greater adherence, but only up to a point, at which benefits will plateau, and greater benefits among participants whose goal-directed simulations are more vivid, personally-relevant, achievable, and positive.
CONCLUSIONS: This innovative approach overcomes a number of limitations present in prior multidomain dementia prevention trials. Adapting a preference clinical trial that is embedded in a community centre, where participants have autonomy to choose programs to address their modifiable dementia risk factors, has real-world applicability in the global effort to reduce dementia risk.
CITATION:
N.D. Anderson ; D. D’Amico ; S. Rotenberg ; D.R. Addis ; J. Gillen ; D. Moore ; J.A. Furlano ; B. Tan ; M. Binns ; M. Santarossa ; H. Chertkow ; for the Canadian Consortium on Neurodegeneration in Aging (CCNA) CAN-THUMBS UP Study Group (2024): Validation of a Community-Based Approach Toward Personalized Dementia Risk Reduction: The Kimel Family Centre for Brain Health and Wellness. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.98
THE ALZMATCH PILOT STUDY - FEASIBILITY OF REMOTE BLOOD COLLECTION OF PLASMA BIOMARKERS FOR PRECLINICAL ALZHEIMER’S DISEASE TRIALS
S. Walter, O. Langford, G.A. Jimenez-Maggiora, S. Abdel-Latif, R.A. Rissman, J.D. Grill, J. Karlawish, A. Atri, S. Bruschi, K. Hussen, M.C. Donohue, G.A. Marshall, G. Jicha, M. Racke, R.S. Turner, C.H. van Dyck, V. Venkatesh, K.E. Yarasheski, R. Sperling, J. Cummings, P.S. Aisen, R. Raman
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BACKGROUND: Advances in plasma biomarkers to detect Alzheimer’s disease (AD) biology allows researchers to improve the efficiency of participant recruitment into preclinical trials. Recently, protein levels of plasma amyloid-beta and tau proteins have been shown to be predictive of elevated amyloid in brain. Online registries, such as the Alzheimer’s Prevention Trials (APT) Webstudy, include and follow participants using remote assessments to facilitate efficient screening and enrollment of large numbers of individuals who may be at higher risk for AD.
OBJECTIVES: The AlzMatch Pilot Study investigated the feasibility of recruiting individuals from an online registry for blood sample collection at community-based phlebotomy centers and plasma biomarker quantification to assess an individual’s eligibility for AD preclinical trials.
DESIGN: Pilot feasibility study with co-primary outcomes.
SETTING: This pilot feasibility study included participants from the APT Webstudy, the remote assessment arm of the Trial-ready cohort for Preclinical and Prodromal AD (TRC-PAD) Platform. Novel design included collection of electronic consent, use of community laboratories for plasma collection, mass spectrometry-based biomarker assay, and telephone communication of plasma biomarker screening eligibility.
PARTICIPANTS: Participants invited to the AlzMatch pilot feasibility study were active in the APT Webstudy, 50 years of age or older, resided within 50 miles of both a Quest Diagnostics Patient Services Center (a national diagnostic laboratory with convenient locations for sample collection and processing) and one of six TRC-PAD vanguard clinical trial sites, had no self-reported dementia diagnosis, were able to communicate in English and engaged with the APT Webstudy within the prior 6 months.
MEASUREMENTS: Primary feasibility outcomes were completion of electronic consent (e-consent) for invited participants and collection of usable blood samples. Additional feasibility outcomes included invitation response rate, plasma biomarker eligibility status (based on amyloid beta-42/40 [Aβ42/40] concentration ratio), ApoE proteotype, and trial inclusion criterion), and completion of telephone contact to learn eligibility to screen for a study.
RESULTS: 300 APT Webstudy participants were invited to consent to the AlzMatch study. The AlzMatch e-consent rate was 39% (n=117) (95% CI of 33.5%-44.5%) overall, which was higher than the expected rate of 25%. Similar consent rates were observed across participants based on self-defined sex (41% Female (n=75), 37% Male (n=42)) and race and ethnicity (37% from underrepresented groups (URG) (n=36), 40% not from URG (n=79)). Among those that consented (n=117), plasma was successfully collected from 74% (n=87) (95% CI of 66%-82%), with similar rates across sex (76% Female (n=57), 71% Male (n=30)) and race and ethnicity (75% URG (n=27) and 75% not from URG (n=59)). 60% (n=51) of participants with plasma biomarker results were eligible to screen for future preclinical AD trials.
CONCLUSION: Electronic consent of participants through an online registry, blood sample collection at community-based centers, plasma biomarker quantification and reporting, and biomarker assessments for study eligibility were all feasible with similar engagement rates across demographic groups. Although this pilot was a small and selective sample, participants engaged and consented at higher than expected rates. We conclude that collecting blood at community laboratories for biomarker analyses may improve accessibility beyond research, and may facilitate broader access for clinical use of AD plasma biomarkers. Based on our results, an expanded version of the AlzMatch study is underway, which involves expanding invitations to additional APT Webstudy participants and clinical trial sites.
CITATION:
S. Walter ; O. Langford ; G.A. Jimenez-Maggiora ; S. Abdel-Latif ; R.A. Rissman ; J.D. Grill ; J. Karlawish ; A. Atri ; S. Bruschi ; K. Hussen ; M.C. Donohue ; G.A. Marshall ; G. Jicha ; M. Racke ; R.S. Turner ; C.H. van Dyck ; V. Venkatesh ; K.E. Yarasheski ; R. Sperling ; J. Cummings ; P.S. Aisen ; R. Raman (2024): The AlzMatch Pilot Study - Feasibility of Remote Blood Collection of Plasma Biomarkers for Preclinical Alzheimer’s Disease Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.101
HEIGHTENED PREVALENCE OF COMMON HOSPITAL-TREATED INFECTIONS PRECEDING DEMENTIA DIAGNOSIS WITH ACCELERATED DEMENTIA ONSET AFTER INFLUENZA
H. Untersteiner, R. Wurm, B. Reichardt, S. Goeschl, E. Berger-Sieczkowski, T. König, T. Parvizi, S. Silvaieh, E. Stögmann
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BACKGROUND: Since the beginning of Alzheimer’s disease research, the hypothesis that infections are to some extent associated with neurodegenerative processes has been tested repeatedly. Epidemiological studies on the associations between infections and dementia have reported conflicting results.
OBJECTIVES: This study analyses common hospital-treated infections (herpes, influenza, intestinal infections, pneumonia, sepsis, urinary tract infections) and their association with subsequent dementia and time until dementia onset.
DESIGN, SETTING, AND PARTICIPANTS: For this nationwide population-based case-control study, the dataset of the Austrian National Health Insurance Association was used, including dementia patients (dementia cohort) and age- and gender-matched non-demented individuals (control cohort). Only subjects with data availability of at least 10 years prior to the index date (date of dementia diagnosis or date of censoring) were included.
MEASUREMENTS: The incidence of six common infections in older adults (herpes, influenza, intestinal infections, pneumonia, sepsis, and urinary tract infections) was analyzed over a period of 10 years before the censoring date.
RESULTS: The study population consists of 58208 subjects (29104 per study cohort), mean age: 81 years, 54% females. Patients of the dementia cohort had suffered from infections significantly more often than patients of the control cohort (6002, 20.6% vs. 4826, 16.6%; p < 0.001). Influenza, urinary tract infections, intestinal infections, and sepsis showed independent positive associations with subsequent dementia diagnosis, irrespective of other comorbidities (odds ratios: 1.26 (95% CI: 1.06-1.49), 1.23 (95% CI: 1.16-1.30), 1.16 (95% CI: 1.07-1.27), 1.17 (95% CI: 1.01-1.37), respectively). Time from infection to dementia diagnosis was shorter after influenza compared to all other infections (median: 3.4 years (95% CI: 3.1-3.7) vs. 6.6 years (95% CI: 6.4-6.8); p < 0.001).
CONCLUSION: This is the first study to assess the association between infections and dementia over such a long minimum reporting period. These results, supported by consistent data from other epidemiological studies, emphasize the critical importance of infection prevention measures, especially for older adults. Further research is crucial to better understand the nature of the relationship between infections and dementia.
CITATION:
H. Untersteiner ; R. Wurm ; B. Reichardt ; S. Goeschl ; E. Berger-Sieczkowski ; T. König ; T. Parvizi ; S. Silvaieh ; E. Stögmann (2024): Heightened Prevalence of Common Hospital-Treated Infections Preceding Dementia Diagnosis with Accelerated Dementia Onset after Influenza. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.92
LOWER INCIDENCE OF DEMENTIA FOLLOWING CANCER DIAGNOSES: EVIDENCE FROM A LARGE COHORT AND MENDELIAN RANDOMIZATION STUDY
D.T. Bassil, B. Zheng, B. Su, D. Kafetsouli, C. Udeh-Momoh, I. Tzoulaki, S. Ahmadi-Abhari, D.C. Muller, E. Riboli, L.T. Middleton
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BACKGROUND: The reported inverse association between cancer and subsequent Alzheimer’s disease and related dementias (ADRD) remains uncertain.
OBJECTIVES: To investigate the association between these common conditions of old age and explore possible causal factors.
DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We conducted a large population-based cohort analysis using data from 3,021,508 individuals aged 60 and over in the UK Clinical Practice Research Datalink (CPRD), over a period up to 30 years (1988-2018). Cox proportional hazards models were fitted to estimate hazard ratios (HR) for risk of dementia associated with previous cancer diagnosis. Competing risk models were employed to account for competing risk of death. Two-sample Mendelian Randomization analysis based on meta-analysis data from large-scale GWAS studies was also conducted.
RESULTS: In the CPRD cohort, 412,903 participants had cancer diagnosis and 230,558 were subsequently diagnosed with dementia over a median follow-up period of 7.9 years. Cancer survivors had a 25% lower risk of developing dementia (HR=0.75, 95% CI:0.74-0.76) after adjustment for potential confounders. Accounting for competing risk of death provided a sub-distribution HR of 0.56 (95% CI:0.55-0.56). Results were consistent for prevalent and incident cancer and different common cancer types. Two-sample Mendelian Randomization analysis, using 357 cancer-related instrumental single-nucleotide polymorphisms (SNPs) revealed evidence of vertical pleiotropy between genetically predicted cancer and reduced risk of Alzheimer’s disease (OR=0.97,95% CI:0.95-0.99).
CONCLUSION: Our results provide strong epidemiological evidence of the inverse association between cancer and risk of ADRD and support the potential causal nature of this association via genetic instruments. Further investigations into the precise underlying biological mechanisms may reveal valuable information for new therapeutic approaches.
CITATION:
D.T. Bassil ; B. Zheng ; B. Su ; D. Kafetsouli ; C. Udeh-Momoh ; I. Tzoulaki ; S. Ahmadi-Abhari ; D.C. Muller ; E. Riboli ; L.T. Middleton (2024): Lower Incidence of Dementia Following Cancer Diagnoses: Evidence from a Large Cohort and Mendelian Randomization Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.135
ASSOCIATION BETWEEN FAMILY HOUSEHOLD INCOME AND COGNITIVE RESILIENCE AMONG OLDER US ADULTS: A CROSSSECTIONAL STUDY
M. Iskandar, J. Martindale, J.P.W. Bynum, M.A. Davis
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Cognitive resilience has emerged as a mechanism that may help explain individual differences in cognitive function associated with aging and/or pathology. It is unknown whether an association exists between family income level and cognitive resilience. We performed a cross-sectional study to estimate the relationship between family income level and high cognitive resilience using the National Health and Nutrition Examination Survey (NHANES) among older adults (age≥60). Logistic regression was used to estimate the association between income level and high cognitive resilience adjusted for other factors. Accounting for differences in education, occupation, and health status, older adults in the highest income category were twice as likely compared to those with very low income to have high cognitive resilience (OR: 1.90, 95% CI: 1.05,3.43). A doseresponse was apparent between income category and high cognitive resilience. The finding that income, above and beyond that of known factors, affects cognitive function is important for future public health strategies that aim to prevent or delay cognitive impairment.
CITATION:
M. Iskandar ; J. Martindale ; J.P.W. Bynum ; M.A. Davis (2024): Association between Family Household Income and Cognitive Resilience among Older US Adults: A Cross-Sectional Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.97
DOES PLAYING MAHJONG BENEFIT OLDER INDIVIDUALS? A SCOPING REVIEW
Z.C.K. Tse, Y. Cao, B.K.H. Chau, M.K. Yeung, C. Leung, D.H.K. Shum
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Playing mahjong is a popular intellectual and social leisure activity in Asian countries. It is culturally believed that this activity is beneficial to cognitive and psychological functioning in older adults. However, empirical evidence of the benefits of playing mahjong is scant and scattered across the Western and Asian literature. This scoping review comprehensively examined previous studies of the relationships between playing mahjong and cognitive, psychological, and functional abilities in older adults, highlighted gaps in the literature, and identified directions for future research. A systematic search of the literature was conducted across thirteen Western and Asian databases. Fifty-three studies, including forty-seven observational and six intervention studies, were identified. Overall, the results of the observational studies suggested that more mahjong-playing experience was associated with better cognitive, psychological, and functional abilities. As an intervention, playing mahjong was found to enhance general cognitive abilities and short-term memory and relieve depressive symptoms. However, because most of the reviewed studies adopted a correlational methodology, the neural mechanism underlying the benefits of playing mahjong awaits further elucidation. The findings of this review suggest that more randomized controlled trials should be conducted to explore the effects of playing mahjong on higher-level cognitive functioning in older populations.
CITATION:
Z.C.K. Tse ; Y. Cao ; B.K.H. Chau ; M.K. Yeung ; C. Leung ; D.H.K. Shum ; (2024): Does Playing Mahjong Benefit Older Individuals? A Scoping Review. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.102
LATER-LIFE COGNITIVE TRAJECTORIES AND RISK OF DEATH: RESULTS FROM A 6-YEAR LONGITUDINAL STUDY OF 7082 CHINESE
Y. Zhao, W. Zhou, M. Xing, L. Zhang, Y. Tong, X. Lv, Y. Ma, W. Li
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BACKGROUND AND OBJECTIVES: To identify cognitive decline trajectories in a Chinese elderly population, explore the associations between these trajectories and mortality, and further identify risk factors related to certain trajectories of cognitive decline.
DESIGN: Prospective cohort study.
SETTING: The group-based trajectory modeling and Cox proportional hazards models were conducted to explore the association between cognitive trajectory groups and mortality, while multinomial logistic regression models were constructed to estimate potential risk factors.
PARTICIPANTS: We included 7082 participants aged 65 years or above in three consecutive but non-overlapping cohorts of the Chinese Longitudinal Healthy Longevity Survey with the Chinese version of the Mini-Mental State Examination up to 6 years. Participants were subsequently followed for a median (IQR) of 2.89 (1.38-3.12) years to obtain their survival status and date of death.
MEASUREMENTS: Chinese version of the Mini-Mental State Examination was used to measure participants’ cognitive function.
RESULTS: Through use of group-based trajectory modeling, we determined three cognitive trajectory groups. Then, after adjusting for confounding factors, we found a monotonic and positive association between cognitive decline and mortality risk. Meanwhile, the association varied among elderly populations in different age groups and BMI categories, but did not differ by sex, smoking, drinking and exercising. Older seniors, females and those with poorer baseline cognitive function and less social participation tended to be more likely to be in the unfavorable trajectory groups.
CONCLUSION: We found that the faster the cognitive decline, the higher the mortality, especially among those aged 65-79 years and those overweight. Our findings suggested the importance of implement better monitoring of the cognitive function of the elderly population.
CITATION:
Y. Zhao ; W. Zhou ; M. Xing ; L. Zhang ; Y. Tong ; X. Lv ; Y. Ma ; W. Li ; (2024): Later-Life Cognitive Trajectories and Risk of Death: Results from a 6-Year Longitudinal Study of 7082 Chinese. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.96
MULTIDOMAIN INTERVENTION FOR THE REVERSAL OF COGNITIVE FRAILTY USING A PERSONALIZED APPROACH (AGELESS TRIAL): RECRUITMENT AND BASELINE CHARACTERISTICS OF PARTICIPANTS
A.M. Ibrahim, D.K.A. Singh, A.F.M. Ludin, P. Subramaniam, C. Ai -Vyrn, N. Ibrahim, H. Haron, A.M. Safien, N.M. Khalid, P. Ponvel, N.H.M. Fadzil, J.M. Hanipah, F. Mangialasche, M. Kivipelto, S. Shahar
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BACKGROUND: Reversal of cognitive frailty through a multidomain intervention is desirable to prevent dementia. AGELESS Trial was conducted to determine the effectiveness of a comprehensive, multidomain intervention on older adults with cognitive frailty in Malaysia. However, conducting a clinical trial, particularly during and after Covid-19, posed unique challenges.
OBJECTIVE: We aimed to investigate the recruitment process and baseline characteristics of the AGELESS Trial participants to better understand an at-risk population and those who agree to participate in an intervention.
DESIGN/SETTING: 24-month, randomized controlled trial.
PARTICIPANTS: Community-dwelling older adults with independent mobility, aged ≥ 60 years, with a mini mental state examination score of 19-25, a clinical dementia rating of 0.5 ≥ 1 Fried’s physical frailty criteria, and < 22 Beck depression inventory.
INTERVENTION: Participants were randomized 1:1 to a structured multidomain intervention consisting of vascular management, diet, exercise, cognitive and psychosocial stimulation, or to the arm, including routine care and general health consultation.
MEASUREMENT: We analyzed the group differences between (1) cognitive frailty and non- cognitive frailty screened subjects, (2) recruited and non-recruited participants, (3) baseline characteristics of participants by arm, (4) adherence to AGELESS intervention at 12 months, and (5) preliminary findings on the effectiveness of the intervention at 12 months.
RESULTS: A total of 957 older adults from two locations, i.e., urban (n = 764) and rural (n = 193) areas, were screened, of whom 38.9% had cognitive frailty and were eligible to participate. Those with cognitive frailty had fewer years of education (B = -0.08; 95%CI = 0.88-0.97; p = 0.002), and lower functioning cognition (B = -0.24; 95%CI = 0.74-0.84; p < 0.001). Among those from urban areas, only 33.1% (n = 106) agreed to participate, particularly those with multimorbidity (B = 0.86; 95%CI = 1.31-4.30; p = 0.01), higher physical activity (B = -1.02; 95%CI = 0.19-0.69; p = 0.002), slower walking speed (B = 1.26; 95%CI = 1.62-7.61; p = 0.001), and higher systolic blood pressure (B = 0.02; 95%CI = 1.00-1.03; p = 0.03). At baseline, participants’ mean age was 68.1±5.6, years of education was 8.3±3.9, body mass index was 27.5±5.3 kg/m2, and mini mental state examination score was 22.7±4.0. Generally, there were no significant differences between the intervention and control groups for the main outcomes, except those in the intervention group had higher body mass index, mid-upper-arm circumference, and waist circumference (p < 0.05 for all parameters). Overall intervention adherence at 12 months was 52.8%, ranging from 52.8%-90.6% for each of the modules. Preliminary analysis of the effectiveness of the intervention at 12 months was positive on most of the cognitive domains, some of the nutrient intake and food groups, physical function, and vascular outcomes (p < 0.05 for all parameters).
CONCLUSION: Despite the challenges posed by the pandemic, screening, recruitment, and 12-month intervention delivery were achieved in a Malaysian multidomain preventive randomized controlled trial in older adults at risk of dementia, with a satisfactory adherence rate and cognitive benefits at 12 months.
CITATION:
A.M. Ibrahim ; D.K.A. Singh ; A.F.M. Ludin ; P. Subramaniam ; C. Ai -Vyrn ; N. Ibrahim ; H. Haron ; A.M. Safien ; N.M. Khalid ; P. Ponvel ; N.H.M. Fadzil ; J.M. Hanipah ; F. Mangialasche ; M. Kivipelto ; S. Shahar (2024): Multidomain Intervention for the Reversal of Cognitive Frailty Using a Personalized Approach (AGELESS Trial): Recruitment and Baseline Characteristics of Participants. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.111
MENDELIAN RANDOMIZATION ANALYSIS TO ASSESS WHETHER MAGNETIC RESONANCE IMAGING SIGNS OF CEREBRAL SMALL VESSEL DISEASE CAN CAUSE COGNITIVE DECLINE AND DEMENTIA
L. Liu, Q. Shen, D. Zhang, Y. Bao, F. Xu, H. Huang, Y. Xu
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OBJECTIVE: Cognitive decline and dementia have been linked to cerebral small vessel disease, so we explored using Mendelian randomization whether cerebral small vessel disease visible as 10 neuroimaging signs may cause cognitive decline and dementia.
METHODS: We analyzed publicly available data from genome-wide association studies using two-sample Mendelian randomization involving inverse variance weighting, weighted median, MR-Egger, and MR-PRESSO approaches.
RESULTS: Mendelian randomization suggested that cognitive decline can be caused by lacunar stroke (inverse variance weighting, β = -0.012, 95% CI -0.024 to -0.001, P = 0.033). Furthermore, an elevated burden of white matter hyperintensities was associated with an increased risk of Dementia due to Parkinson’s disease (inverse variance weighting, OR 2.035, 95% CI 1.105 to 3.745, P = 0.023). Notably, no significant associations were observed between neuroimaging markers of Cerebral Small Vessel Disease and other types of dementia.
CONCLUSION: This Mendelian randomization study provides evidence that lacunar stroke and white matter lesions can cause cognitive decline, and that white matter hyperintensity may increase risk of dementia due to Parkinson’s disease. These results underscore the need for further investigations into the neurocognitive effects of cerebral small vessel disease.
CITATION:
L. Liu ; Q. Shen ; D. Zhang ; Y. Bao ; F. Xu ; H. Huang ; Y. Xu (2024): Mendelian Randomization Analysis to Assess Whether Magnetic Resonance Imaging Signs of Cerebral Small Vessel Disease Can Cause Cognitive Decline and Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.95
EVALUATING THE CAUSAL EFFECT OF TYPE 2 DIABETES ON ALZHEIMER’S DISEASE USING LARGE-SCALE GENETIC DATA
D. Liu, A. Baranova, F. Zhang
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BACKGROUND: Alzheimer’s disease (AD) has a high comorbidity with type 2 diabetes (T2D). However, there is still some controversy over whether T2D has a causal impact on AD at present.
OBJECTIVES: We aimed to reveal whether T2D has a causal effect on AD using large-scale genetic data.
METHODS: Firstly, we performed a primary two-sample Mendelian randomization (MR) analysis to assess the potential causal effects of T2D on AD. For this analysis, we used the largest available genome-wide association studies (GWAS) T2D (T2D1, including 80,154 cases and 853,816 controls) and AD (AD1, including 111,326 cases and 677,663 controls) datasets. Additionally, we performed a validation MR analysis using two largely overlapping-sample datasets from FinnGen, including T2D (T2D2, including 57,698 cases and 308,252 controls) and AD (AD2, including 13,393 cases and 363,884 controls). In all MR analyses, the inverse variance-weighted method was used as the primary analysis method, supplemented by the weighted-median and MR-Egger techniques.
RESULTS: In the primary analysis, we found that T2D was not associated with the risk of AD (OR: 0.98, CI: 0.95-1.01, P=0.241). Similarly, no significant association was detected in the validation MR analysis (OR: 0.97, CI: 0.64-1.47, P=0.884).
CONCLUSION: Our findings provide robust evidence that T2D does not have a causal impact on AD. Future studies need to further explore the effect of T2D on the non-AD components of the dementia phenotype.
CITATION:
D. Liu ; A. Baranova ; F. Zhang (2024): Evaluating the Causal Effect of Type 2 Diabetes on Alzheimer’s Disease Using Large-Scale Genetic Data. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.148
METABOLIC SYNDROME STATUS CHANGES AND COGNITIVE FUNCTIONING: INSIGHTS FROM THE LIFELINES COHORT STUDY
I. Frentz, S. Marcolini, C.C.I. Schneider, M.A. Ikram, J. Mondragon, P.P. De Deyn
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BACKGROUND: Metabolic syndrome is associated with increased risk of dementia. Yet, findings on how longitudinal development of metabolic syndrome status affects cognition remain controversial.
OBJECTIVES: This study examines whether individuals with different changes in metabolic syndrome status differ in cognitive functioning. Additionally, the prevalence of metabolic syndrome within the Lifelines population-based study is investigated.
DESIGN: 14609 Lifelines participants (mean age 60.8, 56.4% women) were divided into four groups based on their metabolic syndrome status changes between 2007-2013 (1) and between 2014-2017 (2): without metabolic syndrome (N=10863; absent at 1 and 2), de novo metabolic syndrome (N=1340; absent at 1 and present at 2), remitting metabolic syndrome (N=825; present at 1 and absent at 2), and persistent metabolic syndrome (N=1581; present at 1 and 2). ANCOVA models were employed to assess group differences in psychomotor function, visual attention, visual learning, and working memory assessed using the Cogstate Brief Battery.
RESULTS: Accounting for education, age, sex, and time between examinations, groups did not statistically differ in any of the four cognitive outcomes. The prevalence of metabolic syndrome within the Lifelines population increased with age and differed among men and women.
CONCLUSION: Performance in psychomotor function, visual attention, visual learning, and working memory measured by the Cogstate Brief Battery did not differ between individuals with different changes in metabolic syndrome. The length of metabolic syndrome exposure was unknown, making our results exploratory and calling for future studies addressing this gap.
CITATION:
I. Frentz ; S. Marcolin ; C.C.I. Schneider ; M.A. Ikram ; J. Mondragon ; P.P. De Deyn (2024): Metabolic Syndrome Status Changes and Cognitive Functioning: Insights from the Lifelines Cohort Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.90
FLAVONOID-RICH FRUIT INTAKE IN MIDLIFE AND LATE-LIFE AND ASSOCIATIONS WITH RISK OF DEMENTIA: THE FRAMINGHAM HEART STUDY
C. Lyu, P.F. Jacques, P.M. Doraiswamy, B. Young, A.S. Gurnani, R. Au, P.H. Hwang
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BACKGROUND: Fruits are an important source of flavonoids, and greater intake of dietary flavonoids in older adults has been shown to be associated with decreased risk of dementia. It is unclear whether this relationship is similar or different between younger adults and older adults.
OBJECTIVES: We examined for associations between midlife and late-life intake of flavonoid-rich fruits and incident dementia. We hypothesized that greater total cumulative intake of flavonoid-rich fruits in midlife and late-life adults would be associated with reduced risk of all-cause dementia.
DESIGN: Longitudinal, cohort study design.
SETTING: Framingham Heart Study, which is a longitudinal, multi-generational community-based cohort based in Framingham, Massachusetts, USA.
PARTICIPANTS: Participants from the Framingham Heart Study Offspring cohort were included (n = 2,790) who attended the fifth core exam between 1991 to 1995, and were dementia-free and at least 45 years of age at that time, as well as had valid food frequency questionnaires from the fifth to ninth core exams.
MEASUREMENTS: Consumption of fruits with high flavonoid content or are important contributors to overall flavonoid intake was collected via food frequency questionnaire. Flavonoid-rich fruits from the food frequency questionnaire included raisins or grapes, prunes, bananas, fresh apples or pears, apple juice or cider, oranges, orange juice, grapefruit, grapefruit juice, strawberries, blueberries, and peaches, apricots, or plums. Dementia ascertainment was based on a multidisciplinary consensus committee, and included all-cause dementia and Alzheimer’s disease dementia diagnoses based on research criteria. Cox models were used to examine associations between cumulative fruit intake and incident dementia, stratified by midlife (45-59 years; n = 1,642) and late-life (60-82 years; n = 1,148).
RESULTS: Greater cumulative total fruit intake in midlife, but not late-life, was significantly associated with a 44% decreased risk of all-cause dementia (HR = 0.56; 95% CI = 0.32 – 0.98; p = 0.044). Decreased risk of all-cause dementia was also associated with higher intake of apples or pears in midlife and late-life, as well as higher intake of raisins or grapes in midlife only, and higher intake of oranges, grapefruit, blueberries, and peaches, apricots, or plums in late-life only.
CONCLUSIONS: Among participants from the Framingham Heart Study, greater overall consumption of flavonoid-rich fruits in midlife was associated with reduced risk of dementia, though intake of specific fruits in midlife and late-life may have a protective role against developing dementia. These findings may help to inform future recommendations on when dietary interventions may be most beneficial to healthy brain aging across the life course.
CITATION:
C. Lyu ; P.F. Jacques ; P.M. Doraiswamy ; B. Young ; A.S. Gurnani ; R. Au ; P.H. Hwang (2024): Flavonoid-Rich Fruit Intake in Midlife and Late-Life and Associations with Risk of Dementia: The Framingham Heart Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.116
BACILLUS CALMETTE-GUERIN (BCG) VACCINE IMPACT ON DEMENTIA RISK IN BLADDER CANCER PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS
M. Ibrahim, P. Kim, R. Marawar, K.I. Avgerinos
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BACKGROUND: The BCG vaccine has been traditionally administered to prevent TB. It has been additionally used in bladder cancer patients as a therapy with success. Some observational studies found that bladder cancer patients receiving BCG may have reduced dementia risk, however, the evidence is not conclusive.
OBJECTIVE: To investigate the impact of BCG vaccine on dementia risk in bladder cancer patients.
METHODS: Six databases were searched from inception to January 13, 2024, for published and unpublished studies that examine the association between BCG and dementia risk in bladder cancer patients. We conducted meta-analyses using a random-effects model.
RESULTS: Eight retrospective cohort studies were included in the systematic review and seven in the meta-analyses. Because there were studies with overlapping populations, two separate main analyses were performed reassuring the avoidance of overlap. The first analysis showed that compared to controls, BCG did not reduce dementia risk [5 studies pooled, n=88,852, HR = 0.65, 95% CI (0.40, 1.06), I2 = 85%] whereas there was a marginally significant risk reduction in the second analysis [6 studies pooled, n=70,025, HR = 0.63, 95% CI (0.40, 0.97), I2 = 83%]. Sensitivity analysis excluding the unpublished studies did not affect the outcome importantly. Additional meta-analysis showed that BCG did not reduce the risk of Alzheimer’s disease.
CONCLUSION: This meta-analysis of observational studies found that BCG administration in bladder cancer patients has likely a minimally positive impact on dementia risk if any. To better understand the effect of BCG on dementia, randomized controlled trials are needed.
CITATION:
M. Ibrahim ; P. Kim ; R. Marawar ; K.I. Avgerinos ; (2024): Bacillus Calmette-Guerin (BCG) Vaccine Impact on Dementia Risk in Bladder Cancer Patients: A Systematic Review and Meta-Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.94
JAPANESE SUBGROUP ANALYSES FROM EMERGE AND ENGAGE, PHASE 3 CLINICAL TRIALS OF ADUCANUMAB IN PATIENTS WITH EARLY ALZHEIMER’S DISEASE
Y. Toda, T. Iwatsubo, Y. Nakamura, N. Matsuda, M. Miyata, M. Jin, T. Chen, K. Kuribayashi, Y. Tian, R. Hughes, J. Yamamoto, K.K. Muralidharan, C. Rubel, R.M. Hutchison, S. Budd Haeberlein
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BACKGROUND: Global prevalence and incidence of dementia continue to rise at a rapid rate. There is a need for new Alzheimer’s disease (AD) treatments globally. Aducanumab is a human monoclonal antibody that selectively targets aggregated soluble amyloid beta oligomers and insoluble amyloid beta fibrils. In June 2021, aducanumab was approved by the US Food and Drug Administration for the treatment of AD under the accelerated approval pathway.
OBJECTIVES: We evaluated the efficacy, safety, biomarker and pharmacokinetics (PK) of aducanumab in Japanese subgroups in EMERGE and ENGAGE studies.
DESIGN: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early AD (mild cognitive impairment due to AD or mild AD dementia).
SETTING: These studies involved 348 sites in 20 countries.
PARTICIPANTS: Participants enrolled in Japan included 121 (7.4% of total 1638 in EMERGE) and 100 (6.1% of total 1647 in ENGAGE) patients (aged 50–85 years with confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to AD or mild AD dementia.
INTERVENTION: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (6 or 10 mg/kg target dose) or placebo via IV infusion once every 4 weeks over 76 weeks.
MEASUREMENTS: The primary outcome measure was change from baseline to Week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; biomarker endpoints (amyloid PET and plasma p-tau181); serum PK profiles and immunogenicity.
RESULTS: Results from the Japanese subgroup analyses were generally consistent with those of the overall study population across endpoints, while a lower mean body weight (kg) and a smaller proportion of ApoE ε4 carriers were observed in the Japanese subgroup population. A treatment effect was observed in favor of aducanumab on the primary and secondary efficacy endpoints at Week 78 in EMERGE, but not ENGAGE. The incidence and type of adverse events in the Japanese subgroups were generally comparable to those observed in the overall study population; amyloid related imaging abnormalities (ARIA) were common treatment-related adverse events that appeared to be related to the aducanumab dose. ARIA incidence was generally lower in the Japanese subgroup compared with the overall population. Consistent with the overall data set, a robust dose-dependent decrease in amyloid beta levels as assessed with amyloid-PET and plasma p-tau181 was observed. Serum PK profiles and immunogenicity of aducanumab in Japanese population were consistent with the non-Japanese population.
CONCLUSION: Efficacy, safety, biomarker, and PK profiles of aducanumab were consistent between the Japanese subgroup and the overall population. A positive treatment effect of aducanumab on efficacy endpoints was observed in EMERGE, but not in ENGAGE.
CITATION:
Y. Toda ; T. Iwatsubo ; Y. Nakamura ; N. Matsuda ; M. Miyata ; M. Jin ; T. Chen ; K. Kuribayashi ; Y. Tian ; R. Hughes ; J. Yamamoto ; K.K. Muralidharan ; C. Rubel ; R.M. Hutchison ; S. Budd Haeberlein (2024): Japanese Subgroup Analyses from EMERGE and ENGAGE, Phase 3 Clinical Trials of Aducanumab in Patients with Early Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.106
ASSOCIATIONS OF BLOOD PRESSURE TRAJECTORIES WITH SUBSEQUENT COGNITIVE DECLINE, DEMENTIA AND MORTALITY
Y. Zhu, C. Li, D. Gao, X. Huang, Y. Zhang, M. Ji, F. Zheng, W. Xie
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BACKGROUND: Hypertension may harm cognitive performance, but the potential correlates of longitudinal patterns of blood pressure (BP), especially diastolic BP (DBP), to cognition have been unclear.
OBJECTIVES: To examine long-term BP trajectories in relation to subsequent cognitive decline, incident dementia and all-cause mortality in the general population.
DESIGN: Population-based cohort study.
SETTING: Communities in England.
PARTICIPANTS: The study included 7566 participants from the English Longitudinal Study of Ageing (ELSA).
MEASUREMENTS: BP were measured in 1998, 2004, 2008. Group-based trajectory modeling was used to identify long-term patterns of systolic BP (SBP) and DBP. Outcomes including cognitive function, incident dementia, and all-cause mortality were followed up to 10 years.
RESULTS: Five distinct trajectories were identified for SBP and DBP, respectively. The normal-stable trajectory was used as the reference. For cognitive decline, both SBP and DBP trajectories were independently associated with subsequent cognitive decline, with the fastest decline appeared in the high-stable SBP group of 180 mmHg and the low-stable DBP group of 60 mmHg (both P<0.005). For incident dementia, the multivariable adjusted hazard ratio (HR) was also greatest in high-stable group (4.79, 95% confidence interval: 2.84 to 8.07) across all SBP trajectories. Conversely, low (HR: 1.58) and moderate-low stable (HR: 1.56) DBP trajectories increased dementia risk (both P<0.005). Similar patterns were found in BP trajectories in relation to all-cause mortality.
CONCLUSION: Our study evaluates the potential health impact from different BP trajectories and suggests that controlling long-term SBP and maintaining adequate DBP may be relevant for the current practice to promote cognitive health and extend lifespan.
CITATION:
Y. Zhu ; C. Li ; D. Gao ; X. Huang ; Y. Zhang ; M. Ji ; F. Zheng ; W. Xie ; (2024): Associations of Blood Pressure Trajectories with Subsequent Cognitive Decline, Dementia and Mortality. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.91
ALZHEIMER’S DISEASE LINKAGE TO REAL-WORLD EVIDENCE (AD-LINE) STUDY: LINKING CLAIMS DATA TO PHASE 3 GRADUATE STUDY OF GANTENERUMAB
H. Fillit, S. Seleri Assunção, T. Majda, C.D. Ng, T.M. To, I.M. Abbass, K. Raimundo, C. Wallick, O.V. Tcheremissine
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BACKGROUND: Linking data from clinical trials and real-world claims may improve the robustness of trial data and provide information on the health, economic, and societal impacts of a disease.
OBJECTIVE: To report on the feasibility of linking trial data to Medicare claims data in early symptomatic Alzheimer’s disease (AD) in the US.
DESIGN AND SETTING: Alzheimer’s Disease Linkage to Real-World Evidence (AD-LINE) was a noninterventional cohort study that included participants recruited from the GRADUATE program whose trial data were linked to their Medicare claims.
PARTICIPANTS: AD-LINE participants were 66 years and older with early symptomatic AD (ie, mild cognitive impairment [MCI] due to AD or mild AD dementia) and were enrolled in the GRADUATE program and a Medicare fee-for-service or Medicare Advantage plan.
MEASUREMENTS: The Centers for Medicare & Medicaid Services linked participants’ clinical trial identifiers to their Medicare beneficiary identifiers using a deterministic, exact matching process. Demographics and clinical characteristics of the AD-LINE cohort at baseline were collected. Outcomes measured in this study included healthcare resource utilization derived from Medicare claims data.
RESULTS: In total, 147 participants across 21 US sites were invited to participate and 111 provided informed consent. Of those, 61 patients had linkable data (ie, Medicare beneficiary identifier), Medicare Parts A/B enrollment, and no health maintenance organization (HMO) enrollment in the year before trial entry. Of the 61 participants whose data were analyzed in this study, 30 had MCI due to AD and 31 had mild AD dementia. Participants in the MCI due to AD group had more healthcare resource utilization on average in the baseline period than those in the mild AD dementia group (29.9 [SD, 20.9] vs 24.5 claims [SD, 12.3]). In an ad hoc analysis, a relatively high concordance (85.3%) was seen between the rates of clinically confirmed AD diagnosis and evidence of AD diagnosis in claims data.
CONCLUSION: This linkage process may serve as a proof of concept for researchers interested in linking clinical trial and real-world claims data. The lessons learned from AD-LINE and innovation of data linkage approaches may encourage key stakeholders to link data in the future.
CITATION:
H. Fillit ; S. Seleri Assunção ; T. Majda ; C.D. Ng ; T.M. To ; I.M. Abbass ; K. Raimundo ; C. Wallick ; O.V. Tcheremissine (2024): Alzheimer’s Disease Linkage to Real-World Evidence (AD-LINE) Study: Linking Claims Data to Phase 3 GRADUATE Study of Gantenerumab. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.115
ESTIMATING SOCIO-ECONOMIC STATUS FOR ALZHEIMER’S DISEASE TRIALS
D.M. Rentz, J.D. Grill, D.P. Molina-Henry, G.A. Jicha, M.S. Rafii, A. Liu, R.A. Sperling, P.S. Aisen, R. Raman
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INTRODUCTION: Metrics of a participant’s socioeconomic status (SES) are not routinely collected or standardized in clinical trials. This omission limits the ability to evaluate the generalizability of trial results and restricts clinicians from confidently interpreting the efficacy of new treatments across important sub-populations.
METHODS: We adapted an SES measure of social disparity; the Hollingshead Two Factor Index of Social Position, which combines education and occupation into a single metric. We modernized the 1965 occupations to reflect the 2017 careers tabulated by the US Bureau of Labor Statistics. We currently use this adapted measure in Alzheimer’s Clinical Trials Consortium studies.
RESULTS: We present the revised table of occupations. We found that the collection of SES data using the modified Hollingshead was feasible in a multi-site clinical trial and scores were distributed across all SES strata.
DISCUSSION: The modified Hollingshead provides a standardized method for collecting SES information, enabling data aggregation, monitoring, and reporting.
CITATION:
D.M. Rentz ; J.D. Grill ; D.P. Molina-Henry ; G.A. Jicha ; M.S. Rafii ; A. Liu ; R.A. Sperling ; P.S. Aisen ; R. Raman (2024): Estimating Socio-Economic Status for Alzheimer’s Disease Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.88
SEMORINEMAB PHARMACOKINETICS AND THE EFFECT ON PLASMA TOTAL TAU PHARMACODYNAMICS IN CLINICAL STUDIES
V. Ramakrishnan, B. Bender, J. Langenhorst, M.O. Magnusson, M. Dolton, J. Shim, R.N. Fuji, C. Monteiro, E. Teng, N. Kassir, J. Jin
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BACKGROUND: Semorinemab is a monoclonal antibody that targets the N-terminal domain of the tau protein that is in clinical development for the treatment of Alzheimer’s disease.
OBJECTIVES: To perform model-based evaluations of the observed pharmacokinetics in serum and the total plasma tau target-engagement dynamics from clinical studies evaluating semorinemab.
DESIGN: The observed semorinemab pharmacokinetics and plasma tau target engagement from phase 1 and 2 clinical studies were modeled using a non-linear mixed effect target-mediated drug disposition model. The model was simulated to understand target engagement at clinical dose levels.
SETTINGS AND PARTICIPANTS: The clinical studies testing semorinemab were evaluated in healthy volunteers, subjects with prodromal-to-mild Alzheimer’s disease, and subjects with mild-to-moderate Alzheimer’s disease. The data included a total of 8430 semorinemab serum concentrations and 4772 total tau protein plasma concentrations from 463 subjects treated with a range of single and multiple doses of semorinemab.
MEASUREMENTS: Serum concentrations of semorinemab and the total plasma tau concentrations were measured after administration of a range of doses of semorinemab to subjects with Alzheimer’s disease. A sensitivity analysis was performed wherein key target-mediated drug disposition model parameters were estimated separately between healthy volunteers, subjects with prodromal-to-mild Alzheimer’s disease, and subjects with mild-to-moderate Alzheimer’s disease.
RESULTS: Serum concentrations of semorinemab were consistent across studies and showed a dose-proportional increase across the evaluated dose range. The pharmacokinetic profile was comparable between healthy volunteers and subjects with Alzheimer’s disease. Total plasma tau concentrations increased in a dose-dependent non-linear manner upon semorinemab administration. The target-mediated drug disposition model adequately described the serum pharmacokinetics and protein dynamics with an estimated antibody-ligand binding strength, Kss, of 42.7 nM. The estimated values of clearance and central volume of distribution were 0.109 L/day/70 kg and 2.95 L/70 kg, respectively, and were consistent with typical values for IgG mAbs. In the sensitivity analysis, Kss (32 nM) and baseline tau protein (0.30 µM) were estimated to be lower for healthy volunteers compared to subjects with Alzheimer’s disease but were comparable between subjects with Alzheimer’s disease of different severities (Kss: 52-57 nM, baseline tau: 0.44-0.47 µM). The models suggested that peripheral target engagement was over 90% at the clinical doses in each of the diagnostic subgroups.
CONCLUSION: Our target-mediated drug disposition model adequately described the serum pharmacokinetics and the peripheral non-linear increase with dose of the total tau. The model confirmed that these dose-response relationships were consistent across populations of healthy volunteers and subjects with different severities of Alzheimer’s disease.
CITATION:
V. Ramakrishnan ; B. Bender ; J. Langenhorst ; M.O. Magnusson ; M. Dolton ; J. Shim ; R.N. Fuji ; C. Monteiro ; E. Teng ; N. Kassir ; J. Jin (2024): Semorinemab Pharmacokinetics and The Effect on Plasma Total Tau Pharmacodynamics in Clinical Studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.146
META ANALYSIS OF THE CORRELATION BETWEEN PERIODONTAL HEALTH AND COGNITIVE IMPAIRMENT IN THE OLDER POPULATION
Y.-D. Fu, C.-L. Li, C.-L. Hu, M.-D. Pei, W.-Y. Cai, Y.-Q. Li, L. Xu, Y. Zeng
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OBJECTIVE: To explore the correlation between periodontal health and cognitive impairment in the older population to provide the evidence for preventing cognitive impairment from the perspective of oral health care in older adults.
METHODS: A comprehensive search was conducted in PubMed, Embase, the Cochrane Library, the Web of Science, the China National Knowledge Infrastructure, Wanfang Data, the China Science and Technology Journal Database, and the China Biomedical Literature Database, to include both cross-sectional and longitudinal cohort studies on the association between periodontal health and cognitive impairment in older adults. The search was completed in April 2023. Following quality assessment and data organization of the included studies, meta-analysis was performed using Review Manager 5.4.
RESULTS: Twenty-two studies involving a total of 4,246,608 patients were included to comprehensively assess periodontal health from four dimensions (periodontitis, tooth loss, occlusal support, and masticatory ability), with the outcome variable of cognitive impairment (including mild cognitive impairment, Alzheimer’s disease and all-cause dementia). Meta-analysis showed that, compared to those of periodontally healthy older adults, the risk of cognitive impairment in older adults with poor periodontal health, after adjusting for confounders, was significantly greater for those with periodontitis (OR=1.45, 95% CI: 1.20-1.76, P<0.001), tooth loss (OR=1.80, 95% CI: 1.50-2.15, P<0.001), compromised occlusal support (OR=1.87, 95% CI: 1.29-2.70, P=0.001), and reduced masticatory ability (OR=1.39, 95% CI: 1.11-1.75, P=0.005). The risk of cognitive impairment was higher in older adults with low-dentition than in those with high-dentition. Subgroup analysis revealed older individuals with fewer remaining teeth were at a higher risk of developing cognitive impairment compared to those with more remaining teeth, as shown by the comparison of number of teeth lost (7-17 teeth compared to 0-6 teeth) (OR=1.64, 95% CI: 1.13-2.39, P=0.01), (9-28 teeth compared to 0-8 teeth) (OR=1.13, 95% CI: 1.06-1.20, P<0.001), (19-28 teeth compared to 0-18 teeth) (OR=2.52, 95% CI: 1.32-4.80, P=0.005), and (28 teeth compared to 0-27 teeth) (OR=2.07, 95% CI: 1.54-2.77, P<0.001). In addition, tooth loss in older adults led to a significantly increased risk of mild cognitive impairment (OR=1.66, 95% CI: 1.43-1.91, P<0.001) and all-cause dementia (OR=1.35, 95% CI: 1.11-1.65, P=0.003), although the correlation between tooth loss and the risk of Alzheimer’s disease was not significant (OR=3.89, 95% CI: 0.68-22.31, P=0.13).
CONCLUSION: Poor periodontal health, assessed across four dimensions (periodontitis, tooth loss, occlusal support, and masticatory ability), represents a significant risk factor for cognitive impairment in older adults. The more missing teeth in older adults, the higher risk of developing cognitive impairment, with edentulous individuals particularly susceptible to cognitive impairment. While a certain degree of increased risk of Alzheimer’s disease was observed, no significant association was found between tooth loss and the risk of developing Alzheimer’s disease. Enhancing periodontal health management and delivering high-quality oral health care services to older adults can help prevent cognitive impairment.
CITATION:
Y.-D. Fu ; C.-L. Li ; C.-L. Hu ; M.-D. Pei ; W.-Y. Cai ; Y.-Q. Li ; L. Xu ; Y. Zeng (2024): Meta Analysis of the Correlation between Periodontal Health and Cognitive Impairment in the Older Population. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.87
A STATISTICAL FRAMEWORK FOR ASSESSING THE RELATIONSHIP BETWEEN BIOMARKERS AND CLINICAL ENDPOINTS IN ALZHEIMER’S DISEASE
T. Chen, R.M. Hutchison, C. Rubel, J. Murphy, J. Xie, P. Montenigro, W. Cheng, K. Fraser, G. Dent, S. Hendrix, O. Hansson, P. Aisen, Y. Tian, J. O’Gorman
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Changes in biomarker levels of Alzheimer’s disease (AD) reflect underlying pathophysiological changes in the brain and can provide evidence of direct and downstream treatment effects linked to disease modification. Recent results from clinical trials of anti–amyloid β (Aβ) treatments have raised the question of how to best characterize the relationship between AD biomarkers and clinical endpoints. Consensus methodology for assessing such relationships is lacking, leading to inconsistent evaluation and reporting. In this review, we provide a statistical framework for reporting treatment effects on early and late accelerating AD biomarkers and assessing their relationship with clinical endpoints at the subject and group levels. Amyloid positron emission tomography (PET), plasma p-tau, and tau PET follow specific trajectories during AD and are used as exemplar cases to contrast biomarkers with early and late progression. Subject-level correlation was assessed using change from baseline in biomarkers versus change from baseline in clinical endpoints, and interpretation of the correlation is dependent on the biomarker and disease stage. Group-level correlation was assessed using the placebo-adjusted treatment effects on biomarkers versus those on clinical endpoints in each trial. This correlation leverages the fundamental advantages of randomized placebo-controlled trials and assesses the predictivity of a treatment effect on a biomarker or clinical benefit. Harmonization in the assessment of treatment effects on biomarkers and their relationship to clinical endpoints will provide a wealth of comparable data across clinical trials and may yield new insights for the treatment of AD.
CITATION:
T. Chen ; R.M. Hutchison ; C. Rubel ; J. Murphy ; J. Xie ; P. Montenigro ; W. Cheng ; K. Fraser ; G. Dent ; S. Hendrix ; O. Hansson ; P. Aisen ; Y. Tian ; J. O’Gorman (2024): A Statistical Framework for Assessing the Relationship between Biomarkers and Clinical Endpoints in Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.126
THE RELATIONSHIP BETWEEN HISTORY OF TRAUMATIC BRAIN INJURY AND LONGITUDINAL CHANGES IN CORTICAL THICKNESS AMONG PATIENTS WITH ALZHEIMER’S DISEASE
G.M. D’Souza, N.W. Churchill, D.X. Guan, M.A. Khoury, S.J. Graham, S. Kumar, C.E. Fischer, T.A. Schweizer
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BACKGROUND: There has been little direct examination of how traumatic brain injury (TBI) affects the rate of neurodegeneration for individuals with Alzheimer’s disease (AD).
METHODS: The study examined 89 cognitively normal adults (65 with and 24 without prior TBI) and 65 with AD (16 with and 49 without prior TBI). Cortical thickness was quantified from T1-weighted MRI scans at baseline and follow-up (mean interval 33.4 months). Partial least squares analysis was used to evaluate the effects of AD and TBI history on the longitudinal change in cortical thickness.
RESULTS: Significant group effects were identified throughout the frontal and temporal cortices. Comparison of the AD groups to their control cohorts showed greater relative atrophy for the AD cohort with prior TBI.
CONCLUSION: These results indicate that a history of TBI exacerbates longitudinal declines in cortical thickness among AD patients, providing new insights into the shared pathomechanisms between these neurological conditions.
CITATION:
G.M. D’Souza ; N.W. Churchill ; D.X. Guan ; M.A. Khoury ; S.J. Graham ; S. Kumar ; C.E. Fischer ; T.A. Schweizer (2024): The Relationship between History of Traumatic Brain Injury and Longitudinal Changes in Cortical Thickness among Patients with Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.86
CLINICAL MEANINGFULNESS IN ALZHEIMER’S DISEASE CLINICAL TRIALS. A REPORT FROM THE EU-US CTAD TASK FORCE
D. Angioni, J. Cummings, C.J. Lansdall, L. Middleton, C. Sampaio, S. Gauthier, S. Cohen, R.C. Petersen, D.M. Rentz, A.M. Wessels, S.B. Hendrix, F. Jessen, M.C. Carrillo, R.S. Doody, M. Irizarry, J.S. Andrews, B. Vellas, P. Aisen
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Recent positive results of three phase III anti-amyloid monoclonal antibody trials are transforming the landscape of disease-modifying therapeutics for Alzheimer’s disease, following several decades of failures. Indeed, all three trials have met their primary endpoints. However, the absolute size of the benefit measured in these trials has generated a debate on whether the change scores observed on clinical outcome assessments represent a clinically meaningful benefit to patients. An evidence-based conclusion is urgently required to inform decision-making related to the approval, reimbursement, and ultimately, the management of emerging therapies in clinical practice. The EU-US CTAD Task Force met in Boston to address this important question. The current state-of-the-art knowledge for interpreting clinical meaningfulness of AD clinical trial results, including the point of view of patients and study partners on what is clinically meaningful, was discussed and is summarized here. A combination of methodologies to address the challenges emerged. There remain gaps in the understanding of clinical meaningfulness that only long-term longitudinal studies will be able to address.
CITATION:
D. Angioni ; J. Cummings ; C.J. Lansdall ; L. Middleton ; C. Sampaio ; S. Gauthier ; S. Cohen ; R.C. Petersen ; D.M. Rentz ; A.M. Wessels ; S.B. Hendrix ; F. Jessen ; M.C. Carrillo ; R.S. Doody ; M. Irizarry ; J.S. Andrews ; B. Vellas ; P. Aisen (2024): Clinical Meaningfulness in Alzheimer’s Disease Clinical Trials. A Report from the EU-US CTAD Task Force. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.112
MEDICAL COSTS AND CAREGIVER BURDEN OF DELIVERING DISEASE-MODIFYING ALZHEIMER’S TREATMENTS WITH DIFFERENT DURATION AND ROUTE OF ADMINISTRATION
T. Ozawa, G. Franguridi, S. Mattke
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BACKGROUND: Multiple disease modifying treatment for Alzheimer’s disease are currently in clinical development or have been recently approved for use. They have vastly different treatment properties but so far, little work has been done to quantify the impact of treatment properties on the treatment’s value in terms of medical and social care costs and caregiver burden.
OBJECTIVES: This study aims to analyze how the mode of treatment administration, treatment frequency and duration, and monitoring requirements affect the value of disease modifying treatments. In order to isolate these effects, we compare five hypothetical disease modifying treatments with equal efficacy and safety: (1) chronic bi-weekly intravenous infusion, (2) chronic four-weekly intravenous infusion, (3) 52 weeks fixed duration four-weekly intravenous infusion, (4) chronic subcutaneous injections, and (5) chronic oral prescription on their direct medical costs, caregiver burden, and preservation of treatment value.
DESIGN: Survey of Alzheimer’s disease treatment clinics and retrospective data analysis.
SETTING: United States.
MEASUREMENTS: Direct medical cost and caregiver burden of treatment administration and monitoring compared to gross treatment benefit.
RESULTS: Chronic bi-weekly infusion treatment had the highest direct medical cost ($45,208) and caregiver burden ($6,095), reducing the treatment value by 44%, while oral treatment with the lowest direct medical cost ($1,983) and caregiver burden ($457) reduced the treatment value by only 2%. Substantial caregiver burden was reported from the survey, with a reported average of 2.3 hours for an office visit and infusion, 44 minutes of round-trip travel time, and 78% of patients being accompanied by a caregiver for treatment.
CONCLUSION: Burden of chronic intravenous treatments exceed the gross medical and social care cost savings and value of caregiver benefit. The results suggest the need for less complex treatments that require fewer clinic visits to preserve the economic value of disease modifying treatments.
CITATION:
T. Ozawa ; G. Franguridi ; S. Mattke (2024): Medical Costs and Caregiver Burden of Delivering Disease-Modifying Alzheimer’s Treatments with Different Duration and Route of Administration. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.81
PROGRESS IN THE TREATMENT OF ALZHEIMER’S DISEASE IS NEEDED – POSITION STATEMENT OF EUROPEAN ALZHEIMER’S DISEASE CONSORTIUM (EADC) INVESTIGATORS
F. Jessen, M.G. Kramberger, D. Angioni, D. Aarsland, M. Balasa, K. Bennys, M. Boada, M. Boban, A. Chincarini, L. Exalto, A. Felbecker, K. Fliessbach, G.B. Frisoni, A.J. Garza-Martínez, T. Grimmer, B. Hanseeuw, J. Hort, A. Ivanoiu, S. Klöppel, L. Krajcovicova, B. McGuinness, P. Mecocci, A. de Mendonca, A. Nous, P.-J. Ousset, C. Paquet, R. Perneczky, O. Peters, M. Tabuas-Pereira, F. Piazza, D. Plantone, M. Riverol, A. Ruiz, G. Sacco, I. Santana, N. Scarmeas, E. Solje, E. Stefanova, S. Sutovsky, W. van der Flier, T. Welsh, A. Wimo, B. Winblad, L. Frölich, S. Engelborghs
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β-amyloid-targeting antibodies represent the first generation of effective causal treatment of Alzheimer’s disease (AD) and can be considered historical research milestones. Their effect sizes, side effects, implementation challenges and costs, however, have stimulated debates about their overall value. In this position statement academic clinicians of the European Alzheimer’s Disease Consortium (EADC) discuss the critical relevance of introducing these new treatments in clinical care now. Given the complexity of AD it is unlikely that molecular single-target treatments will achieve substantially larger effects than those seen with current β-amyloid-targeting antibodies. Larger effects will most likely only be achieved incrementally by continuous optimization of molecular approaches, patient selection and combinations therapies. To be successful in this regard, drug development must be informed by the use of innovative treatments in real world practice, because full understanding of all facets of novel treatments requires experience and data of real-world care beyond those of clinical trials. Regarding the antibodies under discussion we consider their effects meaningful and potential side effects manageable. We assume that the number of eventually treated patient will only be a fraction of all early AD patients due to narrow eligibility criteria and barriers of access. We strongly endorse the use of these new compound in clinical practice in selected patients with treatment documentation in registries. We understand this as a critical step in advancing the field of AD treatment, and in shaping the health care systems for the new area of molecular-targeted treatment of neurodegenerative diseases.
CITATION:
F. Jessen ; M.G. Kramberger ; D. Angioni ; D. Aarsland ; M. Balasa ; K. Bennys ; M. Boada ; M. Boban ; A. Chincarini ; L. Exalto ; A. Felbecker ; K. Fliessbach ; G.B. Frisoni ; A.J. Garza-Martínez ; T. Grimmer ; B. Hanseeuw ; J. Hort ; A. Ivanoiu ; S. Klöppel ; L. Krajcovicova ; B. McGuinness ; P. Mecocci ; A. de Mendonca ; A. Nous ; P.-J. Ousset ; C. Paquet ; R. Perneczky ; O. Peters ; M. Tabuas-Pereira ; F. Piazza ; D. Plantone ; M. Riverol ; A. Ruiz ; G. Sacco ; I. Santana ; N. Scarmeas ; E. Solje ; E. Stefanova ; S. Sutovsky ; W. van der Flier ; T. Welsh ; A. Wimo ; B. Winblad ; L. Frölich ; S. Engelborghs ; ; (2024): Progress in the Treatment of Alzheimer’s Disease Is Needed – Position Statement of European Alzheimer’s Disease Consortium (EADC) Investigators. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.153
RISK OF DEMENTIA IN KOREAN VIETNAM WAR VETERANS
W. Lee, S. Lee, S.-K. Kang, W.-J. Choi
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BACKGROUND: The number of cases of all types of dementia is increasing, and a significant increase in prevalence has been noted among veterans. Evidence of an association between dementia and exposure to chemicals such as Agent Orange from the Vietnam War is still limited, and there is a reported lack of awareness.
OBJECTIVE: This study aimed to investigate the risk of dementia among Vietnam War veterans in Korea.
DESIGN: This retrospective longitudinal study compared the incidence of dementia between Vietnam War veterans and the general population.
SETTING: This study used data from the nationally representative Korean Vietnam War Veterans’ Health Study Cohort, a combined dataset sourced from the Ministry of Patriots and Veterans Affairs in Korea and the National Health Insurance Sharing Service database.
PARTICIPANTS: There were 191,272 Vietnam War veterans and 1,000,320 people of different ages, sexes, and residences. matched control in 2002. The total number of person-years were 18,543,181.
MEASUREMENTS: The dementia group included participants who had visited a medical facility with any of the following ICD-10 codes in the follow-up periods: “F00 Dementia in Alzheimer’s disease,” “F01 Vascular dementia,” “F02 Dementia in other diseases classified elsewhere,” or “F03 Unspecified dementia.”
RESULTS: The incidence rate ratio for all types of dementia was 1.16, with higher ratios observed for vascular and unspecified dementia, particularly in the younger age groups. There was a significant increase in the risk of dementia, Alzheimer’s disease, vascular dementia, and unspecified dementia.
CONCLUSION: Vietnam War veterans showed an increased risk for all types of dementia. These findings are hypothesized to be due to the effects of the chemicals used during the Vietnam War, which can cause a variety of neurodegenerative diseases. Further studies are warranted to investigate the potential health determinants related to the Vietnam War, focusing on the neurodegenerative effects.
CITATION:
W. Lee ; S. Lee ; S.-K. Kang ; W.-J. Choi ; (2024): Risk of Dementia in Korean Vietnam War Veterans. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.84
VALIDATION OF AN ULTRA-SENSITIVE METHOD FOR QUANTITATION OF PHOSPHO-TAU 217 (PTAU217) IN HUMAN PLASMA, SERUM, AND CSF USING THE ALZPATH PTAU217 ASSAY ON THE QUANTERIX HD-X PLATFORM
H. Zhang, J. Liu, N. Zhang, A. Jeromin, Z.J. Lin
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BACKGROUND: Both blood (plasma and serum) and CSF tau phosphorylated at Threonine 217 (pTau217) have been shown to be able to discriminate early to mild Alzheimer’s disease (AD) from non-AD neurodegenerative disorders and healthy controls with high sensitivity and specificity.
OBJECTIVES: We report the full validation of the ALZpath ultra-sensitive pTau217 research-use only (RUO) assays for human EDTA plasma, serum, and CSF using the Quanterix Simoa HD-X platform, in support of clinical trials and early diagnosis of Alzheimer’s disease.
METHODS: The ALZpath pTau217 Simoa Advantage v2 kit from ALZpath/Quanterix was used for method development and validation of pTau217 in human plasma, serum, and CSF. All three method validations have followed the 2018 FDA BMV and 2022 ICH M10 guidelines.
RESULTS: Validation of pTau217 quantitation in human plasma, serum, and CSF demonstrated that the validated pTau217 assay has an analytical LLOQ of 0.00977 pg/mL. It is one of the most sensitive assays with a minimal required sample volume of 33.3 µl for plasma and serum, and 5 µl for CSF, and is relatively cost-effective, compared to the currently published data. The minimum required dilution (MRD) for plasma, serum, and CSF were determined. The analyte passed short-term stability tests. It was also tolerant of moderate hemolytic, and lipemic interferences in plasma and serum. pTau217 was detected in 100% of tested healthy control plasma, 90.0% of healthy control serum, 92.3% of healthy control CSF samples, and 100% of AD plasma and CSF samples. The validated assay was successfully applied in the analysis of AD samples, with data showing dramatic differences in the pTau217 levels between healthy control subjects and AD patients in both plasma and CSF.
CONCLUSION: Validation of the ALZpath pTau217 Simoa assay in human plasma, serum, and CSF demonstrates ultra sensitivity, high accuracy, and assay robustness. Together with other established and sensitive assays for pTau181, GFAP, and NfL, these assays have immediate utility for application in clinical trials and can play a role in the early diagnosis of neurodegenerative diseases.
CITATION:
H. Zhang ; J. Liu ; N. Zhang ; A. Jeromin ; Z.J. Lin ; (2024): Validation of an Ultra-Sensitive Method for Quantitation of Phospho-Tau 217 (pTau217) in Human Plasma, Serum, and CSF using the ALZpath pTau217 Assay on the Quanterix HD-X Platform. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.155
DISEASE-MODIFYING ANTIRHEUMATIC DRUGS AND DEMENTIA PREVENTION: A SYSTEMATIC REVIEW OF OBSERVATIONAL EVIDENCE IN RHEUMATOID ARTHRITIS
C.-Y. Wu, L.Y. Xiong, Y.Y. Wong, S. Noor, G. Bradley-Ridout, W. Swardfager
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BACKGROUND: Many observational studies have examined the association of disease-modifying antirheumatic drugs (DMARDs) with dementia risk, but the evidence has been mixed, possibly due to methodological reasons. This systematic review (PROSPERO: CRD42023432122) aims to assess existing observational evidence and to suggest if repurposing DMARDs for dementia prevention merits further investigation.
METHODS: Four electronic databases up to October 26, 2023, were searched. Cohort or case-control studies that examined dementia risk associated with DMARDs in people with rheumatoid arthritis were included. Risk of bias was evaluated using the Cochrane Collaboration’s Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) criteria. Findings were summarized by individual drug classes and by risk of bias.
RESULTS: Of 12,180 unique records, 14 studies (4 case-control studies, 10 cohort studies) were included. According to the ROBINS-I criteria, there were 2 studies with low risk of bias, 1 study with moderate risk, and 11 studies with serious or critical risk. Among studies with low risk of bias, one study suggested that hydroxychloroquine versus methotrexate was associated with lower incident dementia, and the other study showed no associations of tumor necrosis factor (TNF) inhibitors, tocilizumab, and tofacitinib, compared to abatacept, with incident dementia.
CONCLUSION: Studies that adequately addressed important biases were limited. Studies with low risk of bias did not support repurposing TNF inhibitors, tocilizumab, abatacept or tofacitinib for dementia prevention, but hydroxychloroquine may be a potential candidate. Further studies that carefully mitigate important sources of biases are warranted, and long-term evidence will be preferred.
CITATION:
C.-Y. Wu ; L.Y. Xiong ; Y.Y. Wong ; S. Noor ; G. Bradley-Ridout ; W. Swardfager ; (2024): Disease-Modifying Antirheumatic Drugs and Dementia Prevention: A Systematic Review of Observational Evidence in Rheumatoid Arthritis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.78
PERFORMANCE OF PLASMA BIOMARKERS COMBINED WITH STRUCTURAL MRI TO IDENTIFY CANDIDATE PARTICIPANTS FOR ALZHEIMER’S DISEASE-MODIFYING THERAPY
M. Manjavong, J.M. Kang, A. Diaz, M.T. Ashford, J. Eichenbaum, A. Aaronson, M.J. Miller, S. Mackin, R. Tank, M. Weiner, R. Nosheny, for the Alzheimer’s Disease Neuroimaging Initiative
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BACKGROUND: Recently, two monoclonal antibodies that lower amyloid plaques have shown promising results for the treatment of Mild Cognitive Impairment (MCI) and mild dementia due to Alzheimer’s disease (AD). These treatments require the identification of cognitively impaired older adults with biomarker evidence of AD pathology using CSF biomarkers or amyloid-PET. Previous studies showed plasma biomarkers (plasma Aβ42/Aβ40 and p-tau181) and hippocampal volume from structural MRI correlated with brain amyloid pathology. We hypothesized plasma biomarkers with hippocampal volume would identify patients who are suitable candidates for disease-modifying therapy.
OBJECTIVES: To evaluate the performance of plasma AD biomarkers and hippocampal atrophy to detect MCI or AD with amyloid pathology confirmed by amyloid-PET or CSF biomarkers in ADNI.
DESIGN: A cross-sectional and longitudinal study.
SETTING AND PARTICIPANTS: Data were from the Alzheimer’s Disease Neuroimaging Initiative. Participants were aged 55-90 years old with plasma biomarker and structural MRI brain data.
MEASUREMENTS: The optimum cut-off point for plasma Aβ42/Aβ40, p-tau181, and NFL and the performance of combined biomarkers and hippocampal atrophy for detecting cognitive impairment with brain amyloid pathology were evaluated. The association between baseline plasma biomarkers and clinical progression, defined by CDR-Sum of Boxes (CDR-SB) and diagnostic conversion over two years, was evaluated using a Weibull time-to-event analysis.
RESULTS: A total of 428 participants were included; 167 had normal cognition, 245 had MCI, and 16 had mild AD. Among MCI and AD, 140 participants had elevated amyloid levels by PET or CSF. Plasma Aβ42/Aβ40 provided the best accuracy (sensitivity 79%, specificity 66%, AUC 0.73, 95% CI 0.68-0.77) to detect drug candidate participants at baseline. Combined plasma Aβ42/40, p-tau181, and hippocampal atrophy increased the specificity for diagnosis (96%), but had lower sensitivity (34%), and AUC (0.65). Hippocampal atrophy combined with the abnormal plasma p-tau181 or hippocampal atrophy alone showed high sensitivity to detect clinical progression (by CDR-SB worsening) of the drug-candidate participants within the next 2 years (sensitivity 93% and 89%, respectively).
CONCLUSION: Plasma biomarkers and structural MRI can help identify patients who are currently eligible for anti-amyloid treatment and are likely to progress clinically, in cases where amyloid-PET or CSF biomarkers are not available.
CITATION:
M. Manjavong ; J.M. Kang ; A. Diaz ; M.T. Ashford ; J. Eichenbaum ; A. Aaronson ; M.J. Miller ; S. Mackin ; R. Tank ; M. Weiner ; R. Nosheny ; for the Alzheimer’s Disease Neuroimaging Initiative ; (2024): Performance of Plasma Biomarkers Combined with Structural MRI to Identify Candidate Participants for Alzheimer’s Disease-Modifying Therapy. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.110
VISUAL EVENT-RELATED POTENTIALS UNDER EXTERNAL EMOTIONAL STIMULI AS EARLY SIGNS FOR MILD COGNITIVE IMPAIRMENT
C. Wang, W. Yu, T. Xu, H. Zeng, A. González-Cuello, E. Fernández-Villalba, F. Xu, F. Chu, M.T. Herrero, M. Tao
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BACKGROUND: Alzheimer’s disease (AD) is a neurodegenerative disorder featured by progressive cognitive decline, which manifests in severe impairment of memory, attention, emotional processing and daily activities, leading to significant disability and social burden. Investigation on Mild Cognitive Impairment (MCI), the prodromal and transitional stage between normal aging and AD, serves as a key in diagnosing and slowing down the progression of AD. Numerous effects have been made up to date, however, the attentional mechanisms under different external emotion stimuli in MCI and AD are still unexplored in deep.
OBJECTIVE: To further explore the attentional mechanisms under different external emotion stimuli in both MCI and AD patients.
DESIGN/SETTING/PARTICIPANTS/MEASUREMENTS: In 51 healthy volunteers (Controls, 24 males and 27 females), 52 MCI (19 males and 33 females), and 47 AD (15 males and 32 females) patients, we administered the visual oddball event-related potentials (ERPs) under three types of external emotional stimuli: Neutral, Happiness and Sadness, in which the components N1, P2, N2 and P3 as well as the abnormal cortical activations corresponding to the significant ERP differences in the three groups were observed.
RESULTS: Under all three external emotions, in AD patients, N2 and P3 latencies were significantly prolonged compared to both Controls and MCI. In addition, under Happiness, in MCI, P3 latencies were significantly delayed compared to Controls. Meanwhile, under both Happiness and Sadness, in AD patients, P3 amplitudes were significantly decreased compared to Controls and MCI, respectively. During N2 time window, under Neutral emotion, significant hypoactivation in the right superior temporal gyrus was found in AD patients compared to Controls, and under Happiness, the activation of the right inferior frontal gyrus was significantly attenuated in MCI compared to Controls. Under Sadness, in AD patients, the activation of the right superior frontal gyrus was significantly decreased compared to MCI. During P3 time window, under both Happiness and Sadness, when AD patients compared to MCI, the significantly attenuated activations were located in the right fusiform gyrus and the right middle occipital gyrus, respectively.
CONCLUSION: Our results demonstrated visual attentional deficits under external emotional stimuli in both MCI and AD patients, highlighting the function of Happiness for early detecting MCI, in which the P3 latency and the hypoactivation of right inferior frontal gyrus during N2 time window can be early signs. The current study sheds further light of attentional mechanisms in MCI and AD patients, and indicates the value of emotional processing in the early detection of cognitive dysfunction.
CITATION:
C. Wang ; W. Yu ; T. Xu ; H. Zeng ; A. González-Cuello ; E. Fernández-Villalba ; F. Xu ; F. Chu ; M.T. Herrero ; M. Tao ; (2024): Visual Event-Related Potentials under External Emotional Stimuli as Early Signs for Mild Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.72
PLASMA BIOMARKERS OF ALZHEIMER’S DISEASE AND NEURODEGENERATION ACCORDING TO SOCIODEMOGRAPHIC CHARACTERISTICS AND CHRONIC HEALTH CONDITIONS
H.T. Zheng, Z. Wu, M.M. Mielke, A.M. Murray, J. Ryan
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Ultrasensitive assays have been developed which enable biomarkers of Alzheimer’s disease pathology and neurodegeneration to be measured in blood. These biomarkers can aid in diagnosis, and have been used to predict risk of cognitive decline and Alzheimer’s disease. The ease and cost-effectiveness of blood collections means that these biomarkers could be applied more broadly in population-based screening, however it is critical to first understand what other factors could affect blood biomarker levels. The aim of this review was to determine the extent that sociodemographic, lifestyle and health factors have been associated with blood biomarkers of Alzheimer’s disease and neuropathology. Of the 32 studies included in this review, all but one measured biomarker levels in plasma, and age and sex were the most commonly investigated factors. The most consistent significant findings were a positive association between age and neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), and females had higher GFAP than men. Apolipoprotein ε4 allele carriers had lower Aβ42 and Aβ42/40 ratio. Body mass index was negatively associated with GFAP and NfL, and chronic kidney disease with higher levels of all biomarkers. Too few studies have investigated other chronic health conditions and this requires further investigation. Given the potential for plasma biomarkers to enhance Alzheimer’s disease diagnosis in primary care, it is important to understand how to interpret the biomarkers in light of factors that physiologically impact blood biomarker levels. This information will be critical for the establishment of reference ranges and thus the correct interpretation of these biomarkers in clinical screening.
CITATION:
H.T. Zheng ; Z. Wu ; M.M. Mielke ; A.M. Murray ; J. Ryan ; (2024): Plasma Biomarkers of Alzheimer’s Disease and Neurodegeneration According to Sociodemographic Characteristics and Chronic Health Conditions. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.142
EVALUATING THE PERFORMANCE OF DIFFERENT CRITERIA IN DIAGNOSING AD AND PRECLINICAL AD WITH THE BAYESIAN LATENT CLASS MODEL
X. Wang, G. Niu, J. Zhao, H. Zhu, F. Li, J. Tian, Z. Zhang, G. Chen, Y. He, Q. Gao
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BACKGROUND: The diagnostic criteria for Alzheimer’s disease (AD) should be highly sensitive and specific. Clinicians have varying opinions on the different criteria, including the International Working Group-1 (IWG-1), International Working Group-2 (IWG-2), and AT(N) criteria. Few studies had evaluated the performance of these criteria in diagnosing AD and preclinical AD when the gold standard was absent.
METHODS: We estimated and compared the performance of these criteria in diagnosing AD using data from 908 subjects in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Additionally, 622 subjects were selected to evaluate and compare the performance of IWG-2 and AT(N) criteria in diagnosing preclinical AD. A novel approach, Bayesian latent class models with fixed effect dependent, was utilized to estimate the diagnostic accuracy of these criteria in detecting different AD statuses simultaneously.
RESULTS: The sensitivity of the IWG-1, IWG-2, and AT(N) criteria in diagnosing AD was 0.850, 0.836, and 0.665. The specificity of these criteria was 0.788, 0.746, and 0.747. The IWG-1 criteria had the highest Youden Index in detecting AD. When diagnosing preclinical AD, the sensitivity of the IWG-2 and AT(N) criteria was 0.797 and 0.955. The specificity of these criteria was 0.922 and 0.720. The IWG-2 criteria had the highest Youden Index.
CONCLUSION: IWG-1 was more suitable than the IWG-2 and AT(N) criteria in detecting AD. IWG-2 criteria was more suitable than AT(N) criteria in detecting preclinical AD.
CITATION:
X. Wang ; G. Niu ; J. Zhao ; H. Zhu ; F. Li ; J. Tian ; Z. Zhang ; G. Chen ; Y. He ; Q. Gao (2024): Evaluating the Performance of Different Criteria in Diagnosing AD and Preclinical AD with the Bayesian Latent Class Model. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.71
PREVALENCE ESTIMATION OF DEMENTIA/ALZHEIMER’S DISEASE USING HEALTH AND RETIREMENT STUDY DATABASE IN THE UNITED STATES
A.A. Tahami Monfared, N. Hummel, A. Chandak, A. Khachatryan, R. Zhang, Q. Zhang
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BACKGROUND: Updated prevalence estimates along the continuum of Alzheimer’s disease (AD) can foster a more nuanced and effective approach to managing AD within the current healthcare landscape.
OBJECTIVES: This study aims to estimate the prevalence and severity distribution of dementia/AD (including mild, moderate, and severe stages) and all-cause mild cognitive impairment (MCI) in the United States using data from the Health and Retirement Study (HRS).
DESIGN: Retrospective study.
SETTING: Data from the bi-annual HRS surveys involving in-depth interviews of a representative sample of Americans aged >50 years.
PARTICIPANTS: Dementia/AD and all-cause MCI patients from the 4 most recent HRS surveys (2014, 2016, 2018 and 2020).
MEASUREMENTS: AD was identified based on diagnosis (self-report). Cognitive performance (modified Telephone Interview of Cognitive Status [TICS-m]) scores in the dementia/AD range were also captured; all-cause MCI was similarly identified using the TICS-m. Dementia/AD and MCI prevalence, as well as the distribution by dementia/AD stage (mild, moderate, or severe), were estimated. Sampling weights developed by HRS were applied to ensure the sample’s representativeness of the target population and unbiased estimates for population parameters.
RESULTS: Across the four HRS surveys, the total number of HRS respondents ranged from 15,000 to 21,000 (unweighted); 7,000 to 14,000 had TICS-m scores. The estimated prevalence of AD (all severity categories combined) in the 2014, 2016, 2018, and 2020 HRS surveys was 1.2%, 1.2%, 1.3% and 1.0%, respectively using the diagnosis-based approach; using the cognitive performance-based approach, 23-27% patients had scores in the dementia/AD ranges across the 4 surveys. The estimated prevalence of all-cause MCI was consistently 23% in each survey. In the 2020 survey, the distribution of mild, moderate, and severe disease stages was 34%, 45%, and 21%, respectively, in patients self-reporting an AD diagnosis, and 55%, 40%, and 5%, respectively in all patients meeting TICS-m threshold for dementia/AD.
CONCLUSION: The prevalence of AD diagnosis based on self-report was approximately 1% across the 4 most recent HRS surveys and may reflect the proportion of patients who have actively sought healthcare for AD. Among HRS survey respondents with cognitive scores available, over 20% were in the dementia/AD range. The distribution of disease by stage differed for self-reported AD diagnosis vs dementia/AD based on cognitive scores. Discordance in estimates of dementia/AD and stage distributions underscores a need for better understanding of clinical practice patterns in AD diagnosis, use of clinical assessment tools, and severity classification in the United States. Accurate patient identification is needed, especially early in the AD disease continuum, to allow for timely and appropriate initiation of new anti-amyloid treatments.
CITATION:
A.A. Tahami Monfared ; N. Hummel ; A. Chandak ; A. Khachatryan ; R. Zhang ; Q. Zhang (2024): Prevalence Estimation of Dementia/Alzheimer’s Disease Using Health and Retirement Study Database in the United States. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.114
JPAD Volume 11, N°04 - 2024
EDITORIAL: INTRODUCTION TO THE SPECIAL ISSUE ON THE A4 STUDY
P. Aisen, R. Sperling
J Prev Alz Dis 2024;4(11):801
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CITATION:
P. Aisen ; R. Sperling ; (2024): Editorial: Introduction to the Special Issue on the A4 Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.118
AMYLOID AND TAU PREDICTION OF COGNITIVE AND FUNCTIONAL DECLINE IN UNIMPAIRED OLDER INDIVIDUALS: LONGITUDINAL DATA FROM THE A4 AND LEARN STUDIES
R.A. Sperling, M.C. Donohue, R.A. Rissman, K.A. Johnson, D.M. Rentz, J.D. Grill, J.L. Heidebrink, C. Jenkins, G. Jimenez-Maggiora, O. Langford, A. Liu, R. Raman, R. Yaari, K.C. Holdridge, J.R. Sims, P.S. Aisen, for the A4 and LEARN Study Teams
J Prev Alz Dis 2024;4(11):802-813
Show summaryHide summaryBACKGROUND: Converging evidence suggests that markers of Alzheimer’s disease (AD) pathology in cognitively unimpaired older individuals are associated with high risk of cognitive decline and progression to functional impairment. The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) and Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) Studies enrolled a large cohort of cognitively normal older individuals across a range of baseline amyloid PET levels. Recent advances in AD blood-based biomarkers further enable the comparison of baseline markers in the prediction of longitudinal clinical outcomes.
OBJECTIVES: We sought to evaluate whether biomarker indicators of higher levels of AD pathology at baseline predicted greater cognitive and functional decline, and to compare the relative predictive power of amyloid PET imaging, tau PET imaging, and a plasma P-tau217 assay.
DESIGN: All participants underwent baseline amyloid PET scan, plasma P-tau217; longitudinal cognitive testing with the Primary Alzheimer Cognitive Composite (PACC) every 6 months; and annual functional assessments with the clinical dementia rating (CDR), cognitive functional index (CFI), and activities of daily living (ADL) scales. Baseline tau PET scans were obtained in a subset of participants. Participants with elevated amyloid (Aβ+) on screening PET who met inclusion/exclusion criteria were randomized to receive placebo or solanezumab in a double-blind phase of the A4 Study over 240+ weeks. Participants who did not have elevated amyloid (Aβ-) but were otherwise eligible for the A4 Study were referred to the companion observational LEARN Study with the same outcome assessments over 240+ weeks.
SETTING: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan and Australia.
PARTICIPANTS: Older participants (ages 65-85) who were cognitively unimpaired at baseline (CDR-GS=0, MMSE 25-30 with educational adjustment, and Logical Memory scores within the normal range LMIIa 6-18) were eligible to continue in screening. Aβ+ participants were randomized to either placebo (n=583) or solanezumab (n=564) in the A4 Study. A subset of Aβ+ underwent tau PET imaging in A4 (n=350). Aβ- were enrolled into the LEARN Study (n=553).
MEASUREMENTS: Baseline 18-F Florbetapir amyloid PET, 18-F Flortaucipir tau PET in a subset and plasma P-tau217 with an electrochemiluminescence (ECL) immunoassay were evaluated as predictors of cognitive (PACC), and functional (CDR, CFI and ADL) change. Models were evaluated to explore the impact of baseline tertiles of amyloid PET and tertiles of plasma P-tau217 on cognitive and functional outcomes in the A4 Study compared to LEARN. Multivariable models were used to evaluate the unique and common variance explained in longitudinal outcomes based on baseline predictors, including effects for age, gender, education, race/ethnic group, APOEε4 carrier status, baseline PACC performance and treatment assignment in A4 participants (solanezumab vs placebo).
RESULTS: Higher baseline amyloid PET CL and P-tau217 levels were associated with faster rates of PACC decline, and increased likelihood of progression to functional impairment (CDR 0.5 or higher on two consecutive measurements), both across LEARN Aβ- and A4 Aβ+ (solanezumab and placebo arms). In analyses considering all baseline predictor variables, P-tau217 was the strongest predictor of PACC decline. Among participants in the highest tertiles of amyloid PET or P-tau217, >50% progressed to CDR 0.5 or greater. In the tau PET substudy, neocortical tau was the strongest predictor of PACC decline, but plasma P-tau217 contributed additional independent predictive variance in commonality variance models.
CONCLUSIONS: In a large cohort of cognitively unimpaired individuals enrolled in a Phase 3 clinical trial and companion observational study, these findings confirm that higher baseline levels of amyloid and tau markers are associated with increased rates of cognitive decline and progression to functional impairment. Interestingly, plasma P-tau217 was the best predictor of decline in the overall sample, superior to baseline amyloid PET. Neocortical tau was the strongest predictor of cognitive decline in the subgroup with tau PET, suggesting that tau deposition is most closely linked to clinical decline. These findings indicate that biomarkers of AD pathology are useful to predict decline in an older asymptomatic population and may prove valuable in the selection of individuals for disease-modifying treatments.
CITATION:
R.A. Sperling ; M.C. Donohue ; R.A. Rissman ; K.A. Johnson ; D.M. Rentz ; J.D. Grill ; J.L. Heidebrink ; C. Jenkins ; G. Jimenez-Maggiora ; O. Langford ; A. Liu ; R. Raman ; R. Yaari ; K.C. Holdridge ; J.R. Sims ; P.S. Aisen ; for the A4 and LEARN Study Teams ; (2024): Amyloid and Tau Prediction of Cognitive and Functional Decline in Unimpaired Older Individuals: Longitudinal Data from the A4 and LEARN Studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.122
CHARACTERIZING CLINICAL PROGRESSION IN COGNITIVELY UNIMPAIRED OLDER INDIVIDUALS WITH BRAIN AMYLOID: RESULTS FROM THE A4 STUDY
D.M. Rentz, P.B. Rosenberg, R.A. Sperling, M.C. Donohue, R. Raman, A. Liu, P.S. Aisen, and on behalf of the A4 study team
J Prev Alz Dis 2024;4(11):814-822
Show summaryHide summaryBACKGROUND: Clinical Dementia Rating (CDR) global (CDR-G) and sum of box scores (CDR-SB) are commonly used as primary outcome variables to measure progression or treatment effects in symptomatic Alzheimer disease (AD) clinical trials.
OBJECTIVES: We sought to determine whether the CDR is sensitive to change in pre-symptomatic AD and whether there are specific CDR boxes that are dynamic during the multi-year Anti-Amyloid in Asymptomatic Alzheimer’s Disease (A4) secondary prevention study.
DESIGN: All participants entered the study with a CDR-G of 0. Box scores were examined individually and as composites of cognition (memory, orientation and judgment /problem solving) and function (community affairs and home/ hobbies). A progression in box score was tabulated only when the change occurred at two consecutive visits.
SETTING: The A4 study took place at 67 sites in Australia, Canada, Japan and the United States.
PARTICIPANTS: 1,147 individuals, ages 65-85, were randomized to either placebo (n= 583) or solanezumab (n= 564). All participants received a baseline flobetapir PET scan, an annual CDR, and cognitive testing every 6 months with the Primary Alzheimer Cognitive Composite (PACC) over the course of 240 weeks.
MEASUREMENTS: Generalized estimating equations and generalized least square models were used to explore the modeled mean progression rate in the CDR-G, CDR-SB, individual CDR boxes, and CDR composite scores in the combined solanezumab and placebo groups. Models were refitted to explore the probability of CDR progression in centiloid tertiles of amyloid at baseline (< 46.1 CL, 46.1 to 77.2 CL, > 77.2 CL). All models included effects for age, education, APOEε4 carrier status, baseline amyloid with flobetapir PET, treatment, and time-by-treatment.
RESULTS: There were no statistical differences between the placebo or solanezumab groups in CDR-G, CDR-SB, specific CDR boxes or CDR composite scores over the course of the trial. Changes in judgment/ problem solving were present at baseline and persisted over time, but progression on the CDR memory box and the CDR cognitive composite quickly predominated. Community affairs and home/ hobbies showed little progression. Personal care remained stable. The probability of cognitive and functional progression in CDR boxes began either at the intermediate or advanced amyloid level (46.1 to 77.2 CL, > 77.2 CL), while amyloid at the lowest level (< 46.1 CL) showed relatively little CDR progression.
CONCLUSIONS: The findings suggest that the CDR memory box and the CDR cognitive composite progressed over 240 weeks and were associated with intermediate and advanced stages of amyloid at baseline. Functional changes in community affairs and home/hobbies were relatively stable. These finding suggest that specific CDR box score changes may help refine our measurement of expected treatment effects in future AD prevention trials.
CITATION:
D.M. Rentz ; P.B. Rosenberg ; R.A. Sperling ; M.C. Donohue ; R. Raman ; A. Liu ; P.S. Aisen ; and on behalf of the A4 study team ; (2024): Characterizing Clinical Progression in Cognitively Unimpaired Older Individuals with Brain Amyloid: Results from the A4 Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.123
LONGITUDINAL PHOSPHO-TAU217 PREDICTS AMYLOID POSITRON EMISSION TOMOGRAPHY IN ASYMPTOMATIC ALZHEIMER’S DISEASE
R.A. Rissman, M.C. Donohue, O. Langford, R. Raman, S. Abdel-Latif, R. Yaari, K.C. Holdridge, J.R. Sims, D. Molina-Henry, G. Jimenez-Maggiora, K.A. Johnson, P.S. Aisen, R.A. Sperling, for the A4 and LEARN Study teams
J Prev Alz Dis 2024;4(11):823-830
Show summaryHide summaryBACKGROUND: Blood-based AD biomarkers such as plasma P-tau217 are increasingly used in clinical trials as a screening tool.
OBJECTIVES: To assess the utility of an electrochemiluminescence (ECL) immunoassay in predicting brain amyloid PET status in cognitively unimpaired individuals.
SETTING: Plasma samples collected at baseline, week 12, and week 240 or endpoint originated from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) trial and the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study.
PARTICIPANTS: Both A4 and LEARN enrolled eligible cognitively unimpaired persons 65 to 85 years. Individuals with elevated brain amyloid PET levels were eligible for the A4 Study, while those without elevated brain amyloid PET levels were eligible for the LEARN Study.
INTERVENTION: Participants in the A4 Study received intravenous solanezumab (up to 1600 mg) or placebo every 4 weeks. The LEARN Study is an observational study without intervention.
MEASUREMENTS: Plasma P-tau217 concentration levels from A4 Study participants were measured using an ECL immunoassay. Receiver Operating Characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by ≥22 CL and ≥ 33 CL.
RESULTS: Receiver operating characteristic curve (ROC) analysis indicates high diagnostic value of P-tau217 in individuals with amyloid PET ≥ 20 (Area under the ROC (AUROC): 0.87) and ≥ 33 CL (AUROC: 0.89). Repeated testing with the placebo group taken 12 weeks apart (range: 68 to 143 days) and the LEARN participants taken between 1.4 and 1.75 years resulted in a strong positive correlation (Corr. 0.91 (0.90 to 0.92)).
CONCLUSION: An ECL immunoassay testing plasma P-tau217 accurately predicts amyloid PET positivity in cognitively unimpaired individuals. Our future analyses aim to determine if use of this assay may reduce the screening burden of preclinical individuals into anti-amyloid clinical trials.
CITATION:
R.A. Rissman ; M.C. Donohue ; O. Langford ; R. Raman ; S. Abdel-Latif ; R. Yaari ; K.C. Holdridge ; J.R. Sims ; D. Molina-Henry ; G. Jimenez-Maggiora ; K.A. Johnson ; P.S. Aisen ; R.A. Sperling ; for the A4 and LEARN Study teams ; (2024): Longitudinal Phospho-tau217 Predicts Amyloid Positron Emission Tomography in Asymptomatic Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.134
RELATIONSHIP BETWEEN PLASMA P-TAU217 AND AMYLOID PET IN RACIAL AND ETHNIC UNDERREPRESENTED GROUPS (REURG) COMPARED WITH NON RE-URG IN LEARN AND A4
D. Molina-Henry, O. Langford, M.C. Donohue, R. Raman, P. Aisen, K.A. Johnson, R.A. Rissman, R. Sperling, and the A4 & LEARN Study Teams
J Prev Alz Dis 2024;4(11):831-837
Show summaryHide summarygroups are severely underrepresented in Alzheimer’s disease trials in part due to disproportionate biomarker ineligibility. Evidence from recent studies support plasma phosphorylated tau 217 (P-tau217) as an early marker for brain Aβ pathology and a reliable marker in predicting elevated brain amyloid PET in cognitively unimpaired adults.
OBJECTIVES: To examine whether the relationship between P-tau217 and 18-F florbetapir PET standard uptake value ratios (SUVR) is influenced by race and ethnicity in the Anti-Amyloid treatment in Asymptomatic Alzheimer’s disease (A4) preclinical AD studies.
DESIGN: We conducted a retrospective analysis of A4 clinical trial and the LEARN natural history companion study data to evaluate the relationship between baseline P-tau217 and PET SUVR concentration levels by race and ethnicity.
SETTING: The analysis was conducted on samples from participants enrolled across 65 study sites in the United States and Canada.
PARTICIPANTS: Cognitively unimpaired adults aged 65-85 enrolled at North American sites in the A4 preclinical AD trial, pre-dose, (N=1018), and the LEARN (N=480) study. Participants were grouped into 2 categories, racial and ethnic underrepresented group (RE-URG) and non-RE-URG (nRE-URG) based on self-identification.
MEASUREMENTS: A mixed-effects regression model was fit to determine differences in the relationship between P-tau217 and PET SUVR by race and ethnicity, adjusting for age, and APOE ε4 carrier status.
RESULTS: Results from the linear mixed-effects model support that there was no statistically significant effect of race and ethnicity on the relationship between P-tau217 and PET SUVR.
CONCLUSION: These findings suggest that the relationship between plasma P-tau217 and PET SUVR is the same across race and ethnicity. Future analyses should corroborate these findings in a larger sample and examine whether plasma P-tau217 reflects the differential amyloid prevalence previously reported for other biomarkers of amyloid.
CITATION:
D. Molina-Henry ; O. Langford ; M.C. Donohue ; R. Raman ; P. Aisen ; K.A. Johnson ; R.A. Rissman ; R. Sperling ; and the A4 & LEARN Study Teams ; (2024): Relationship between Plasma P-Tau217 and Amyloid PET in Racial and Ethnic Underrepresented Groups (RE-URG) Compared with Non RE-URG in LEARN and A4. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.124
LONGITUDINAL TRAJECTORIES OF THE COGNITIVE FUNCTION INDEX IN THE A4 STUDY
R.E. Amariglio, J.D. Grill, D.M. Rentz, G.A. Marshall, M.C. Donohue, A. Liu, P.S. Aisen, R.A. Sperling, and the A4 Study team
J Prev Alz Dis 2024;4(11):838-845
Show summaryHide summaryBACKGROUND: The Anti-Amyloid in Asymptomatic Alzheimer’s Disease (A4) Study failed to show a treatment benefit with solanezumab, but the longitudinal consequences of elevated amyloid were observed in study participants with objective decline on the Preclinical Alzheimer Cognitive Composite (PACC) and subjective decline on the combined Cognitive Function Index (participant + study partner CFI), during the trial period.
OBJECTIVES: We sought to expand on previous findings by comparing longitudinal patterns of participant and study partner CFI separately and their associations with the PACC stratified by baseline amyloid tertile over the course of the A4 Study.
DESIGN: Cognitively unimpaired older adult participants and their study partners were independently administered the CFI at screen prior to amyloid PET disclosure and then at 3 subsequent visits (week 48, week 168, week 240) of the study. PACC collected at visits concurrent with CFI administration were also examined longitudinally.
SETTING: The A4 Study was conducted at 67 sites in Australia, Canada, Japan, and the United States.
PARTICIPANTS: 1,147 participants with elevated amyloid based on florbetapir PET were enrolled in the A4 Study and included in these analyses. 583 were on placebo and 564 were treated with solanezumab.
MEASUREMENTS: The PACC was used to assess objective cognitive performance and the CFI was used to assess change in everyday cognitive functioning by the participant and their study partner independently. Amyloid level was characterized by Centiloid tertiles (<46.1 CL, 46.1 to 77.2 CL, >77.2 CL). Participants were aware of their elevated amyloid status, but not their CL tertile, or specific level of amyloid. Longitudinal correlations between participant and study partner CFI and PACC were examined at all visits where assessments were available. The impact of baseline amyloid tertile on CFI and PACC associations was also examined.
RESULTS: Both participant and study partner CFI increased over the duration of the study indicating worsening cognitive functioning. Results did not differ by treatment group. The association between higher CFI and worse PACC for both for participant and study partner became progressively stronger over the course of the study. PACC had a significantly higher correlation with study partner CFI than with participant CFI by week 168. The stronger correlations between study partner CFI and PACC were driven by those in the highest amyloid tertile.
CONCLUSION: Both participant and study partner report captured subtle changes in everyday cognitive functioning for participants with biomarker confirmed and disclosed preclinical AD. Moreover, study partner report was most highly aligned with cognitive decline, particularly among those with the highest amyloid load.
CITATION:
R.E. Amariglio ; J.D. Grill ; D.M. Rentz ; G.A. Marshall ; M.C. Donohue ; A. Liu ; P.S. Aisen ; R.A. Sperling ; and the A4 Study team4 ; (2024): Longitudinal Trajectories of the Cognitive Function Index in the A4 Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.125
CHANGE IN DIGITAL COGNITIVE TEST PERFORMANCE BETWEEN SOLANEZUMAB AND PLACEBO GROUPS IN PRECLINICAL ALZHEIMER’S DISEASE: SECONDARY ANALYSES FROM THE A4 STUDY
K.V. Papp, P. Maruff, D.M. Rentz, M.C. Donohue, A. Liu, P.S. Aisen, R.A. Sperling, on behalf of the A4 Study Team
J Prev Alz Dis 2024;4(11):846-856
Show summaryHide summaryBACKGROUND: Primary results from the Anti-Amyloid in Asymptomatic Alzheimer’s disease Study (A4) suggested no benefit of solanezumab on its primary cognitive outcome, a composite of paper and pencil tests (the Preclinical Alzheimer’s Cognitive Composite; PACC).
OBJECTIVE: To determine whether change in cognitive performance, assessed using the Computerized Cognitive Composite (C3) summary score and C3 individual tests, differed between treatment groups over 240 weeks, differed based on baseline Aβ burden, and tracked with PACC decline.
DESIGN: Longitudinal analysis of cognitive change over 240 weeks on the C3 Summary Score and C3 individual tests between participants randomly assigned to solanezumab at a dose of up to 1600 mg intravenously every 4 weeks versus placebo.
SETTING: The A4 study took place at 67 sites in Australia, Canada, Japan and the United States.
PARTICIPANTS: Cognitively unimpaired older adults (n=1117, Mean Age=71.9, 60.7% female) with elevated brain amyloid levels on 18F-florbetapir positron-emission tomography (PET) at baseline (n=549 in the solanezumab group; n=568 in the placebo group).
MEASUREMENTS: Participants completed the C3 battery and PACC every 6 months. The C3 Summary Score combines the Cogstate Brief Battery (CBB)-One Card Learning, the Behavioral Pattern Separation (BPS) Test- Object- Lure Discrimination Index, and the Face Name Associative Memory Exam (FNAME)- Face-Name Matching.
RESULTS: Change on the C3 Summary Score was moderately correlated with change on the PACC (Spearman’s corr=0.53, 95% CI: 0.49 to 0.57; p<0.001). At 240 weeks, mean change in the C3 Summary Score did not differ between groups; +0.24 in the solanezumab group and +0.27 in the placebo group (mean difference= −0.02; 95% CI: −0.13 to 0.08; p = 0.650). Lack of a treatment effect was similarly observed across most individual C3 tests. Performance on the C3 tests were influenced by level of amyloid burden, where higher levels were associated with worse performance.
CONCLUSION: This study provides corroborating evidence that solanezumab does not slow cognitive decline in preclinical AD as exhibited with a computerized cognitive assessment with some evidence that solanezumab may exacerbate cognition on select digital outcomes. This study also provides important information that amyloid related cognitive change manifests differently on individual C3 tests.
CITATION:
K.V. Papp ; P. Maruff ; D.M. Rentz ; M.C. Donohue ; A. Liu ; P.S. Aisen ; R.A. Sperling ; on behalf of the A4 Study Team ; (2024): Change in Digital Cognitive Test Performance between Solanezumab and Placebo Groups in Preclinical Alzheimer’s Disease: Secondary Analyses from the A4 Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.137
SAFETY PROFILE OF A COGNITIVELY UNIMPAIRED OLDER POPULATION WITH ELEVATED CEREBRAL AMYLOID IN A 4.5- YEAR CLINICAL TRIAL
R. Yaari, K.C. Holdridge, M. Mancini, M.S. Rafii, M. Case, C. Battioui, J.R. Sims, P.S. Aisen, R.A. Sperling, A4 Study Team
J Prev Alz Dis 2024;4(11):857-868
Show summaryHide summaryBACKGROUND: Preclinical Alzheimer’s disease is increasingly studied in clinical trials. Although safety signals are routinely monitored in clinical trial populations with Alzheimer’s disease, it can be challenging to identify new safety signals against background rates of age-related medical comorbidities.
OBJECTIVES: To report detailed safety data from a cognitively unimpaired older population with evidence of elevated cerebral amyloid levels on amyloid positron emission tomography in the placebo arm of a Phase 3 clinical trial.
DESIGN: Phase 3, 4.5-year, multicenter, placebo-controlled trial.
SETTING: Placebo data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study.
PARTICIPANTS: Enrolled participants were aged 65–85 years with a global Clinical Dementia Rating score of 0, a Mini-Mental State Examination score of 25–30, a Wechsler Memory Scale Logical Memory IIa (delayed recall) score of 6–18, and elevated brain amyloid levels on 18F-florbetapir positron emission tomography.
MEASUREMENTS: Study participants who received placebo were followed up with post-baseline safety measures. Assessments included review of concomitant medication and adverse events, the Columbia Suicide Severity Rating Scale, electrocardiograms, and neuroimaging (brain magnetic resonance imaging).
RESULTS: In total, 591 study participants (mean age [standard deviation] 71.9 [5.0] years) were assigned to and received placebo in the A4 study, and were followed up to 240 weeks. Participants were primarily White (93.9%) and from the United States (86.8%); 60.4% were women. The most common serious adverse events (incidence rate per 100 person-years) were pneumonia (incidence rate=0.4; 95% confidence interval=0.2–0.7) and atrial fibrillation (incidence rate=0.4; 95% confidence interval=0.2–0.7). The most common treatment-emergent adverse events were upper respiratory tract infection (incidence rate=10.9; 95% confidence interval=9.4–12.5), fall (incidence rate=7.7; 95% confidence interval=6.6–9.0), and nasopharyngitis (incidence rate=5.8; 95% confidence interval=4.8–6.9). The most common ischemia-related findings on magnetic resonance imaging were subcortical infarction (incidence rate=1.4; 95% confidence interval=1.0–2.0) and acute ischemia (incidence rate=0.6; 95% confidence interval=0.3–1.0). Emergent amyloid-related imaging abnormalities with hemosiderin deposition occurred in 32.8% of participants who received placebo; the primary factor associated with these events during the post-baseline period was the number of microhemorrhages at baseline (odds ratio=349.9; 95% confidence interval=247.6–494.4; adjusted p<0.001).
CONCLUSION: Safety findings in the placebo-treated group from the A4 study provide a robust characterization of expected safety in a clinical trial population with preclinical Alzheimer’s disease. These results may provide context in planning future studies and safety evaluations during ongoing blinded studies in preclinical Alzheimer’s disease.
CITATION:
R. Yaari ; K.C. Holdridge ; M. Mancini ; M.S. Rafii ; M. Case ; C. Battioui ; J.R. Sims ; P.S. Aisen ; R.A. Sperling ; A4 Study Team ; (2024): Safety Profile of a Cognitively Unimpaired Older Population with Elevated Cerebral Amyloid in a 4.5-Year Clinical Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.138
GREATER WHITE MATTER HYPERINTENSITY VOLUME IS ASSOCIATED WITH THE NUMBER OF MICROHEMORRHAGES IN PRECLINICAL ALZHEIMER’S DISEASE
Z. Shirzadi, A.P. Schultz, M. Properzi, R. Yaari, W.-Y.W. Yau, A.M. Brickman, M.S. Rafii, M.C. Donohue, K. Ernstrom, S. Wang, C.R. Jack Jr, S.M. Greenberg, R. Raman, P. Aisen, R.A. Sperling, J.P. Chhatwal, and the A4 Study teams
J Prev Alz Dis 2024;4(11):869-873
Show summaryHide summaryBACKGROUND: Increased white matter hyperintensity (WMH) volume visible on MRI is a common finding in Alzheimer’s disease (AD). We hypothesized that WMH in preclinical AD is associated with the presence of advanced vessel amyloidosis manifested as microhemorrhages (MCH).
OBJECTIVES: 1) To assess the relationship between baseline WMH volume and baseline MCH. 2) To assess the relationship between longitudinal WMH accumulation and last MRI MCH during the double-blind phase of the A4 trial.
DESIGN: A multicenter, randomized, double-blind, placebo-controlled, Phase 3 study comparing solanezumab with placebo given as infusions once every 4 weeks over 4.5 years in subjects with preclinical AD, defined as having evidence of elevated brain amyloid before the stage of clinically evident cognitive impairment, with an optional open-label extension period.
SETTING: Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study.
PARTICIPANTS: A sample of 1157 cognitively unimpaired older adults (mean age = 71.9 years [SD = 4.8 years], 59% women, 59% APOE ε4 carriers).
MEASUREMENTS: A linear regression model was used to assess the impact of baseline MCH amount (0, 1, 2+) on WMH volume. A linear mixed-effects model was used to assess the impact of last MRI MCH on longitudinal WMH. All models were corrected for age, sex, grey matter volume, cortical amyloid PET, APOE ε4 status, and treatment group.
RESULTS: Baseline WMH volume was greater in individuals with more than one MCH compared to those with no MCH (t=4.8, p<0.001). The longitudinal increase in WMH amongst individuals with one (t=2.3, p=0.025) and more than one MCH (t=6.7, p<0.001) at the last MRI was greater than those with no MCH.
CONCLUSION: These results indicate a strong association between WMH and MCH, a common manifestation of cerebral amyloid angiopathy and ARIA-H. These results suggest that increased WMH volume may represent an early sign of vessel amyloidosis, likely prior to the emergence of MCH.
CITATION:
Z. Shirzadi ; A.P. Schultz ; M. Properzi ; R. Yaari ; W.-Y.W. Yau ; A.M. Brickman ; M.S. Rafii ; M.C. Donohue ; K. Ernstrom ; S. Wang ; C.R. Jack Jr ; S.M. Greenberg ; R. Raman ; P. Aisen ; R.A. Sperling ; J.P. Chhatwal ; and the A4 Study teams ; (2024): Greater White Matter Hyperintensity Volume Is Associated with the Number of Microhemorrhages in Preclinical Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.139
PRE-RANDOMIZATION PREDICTORS OF STUDY DISCONTINUATION IN A PRECLINICAL ALZHEIMER’S DISEASE RANDOMIZED CONTROLLED TRIAL
R. Raman, K. Hussen, M.C. Donohue, K. Ernstrom, K.C. Holdridge, O. Langford, D.P. Molina-Henry, A.L. Pierce, J.R. Sims, A. Smith, R. Yaari, P.S. Aisen, R. Sperling, J.D. Grill, and the A4 Study Team
J Prev Alz Dis 2024;4(11):874-880
Show summaryHide summaryBACKGROUND: Participant discontinuation from study treatment in a clinical trial can leave a trial underpowered, produce bias in statistical analysis, and limit interpretability of study results. Retaining participants in clinical trials for the full study duration is therefore as important as participant recruitment.
OBJECTIVE: This analysis aims to identify associations of pre-randomization characteristics of participants with premature discontinuation during the blinded phase of the Anti-Amyloid treatment in Asymptomatic AD (A4) Study.
DESIGN: All A4 trial randomized participants were classified as having prematurely discontinued study during the blinded period of the study for any reason (dropouts) or completed the blinded phase of the study on treatment (completers).
SETTING: The trial was conducted across 67 study sites in the United States, Canada, Japan and Australia through the global COVID-19 pandemic.
PARTICIPANTS: The sample consisted of all 1169 A4 trial randomized participants.
MEASUREMENTS: Pre-randomization demographic, clinical, amyloid PET and genetic predictors of study discontinuation were evaluated using a univariate generalized linear mixed model (GLMM), with discontinuation status as the binary outcome, each predictor as a fixed effect, and site as a random effect to account for differences among study sites in the trial. Characteristics significant at p<0.10 were then included in a multivariable GLMM.
RESULTS: Among randomized participants, 339 (29%) discontinued the study during the blinded period (median follow-up time in trial: 759 days). From the multivariable analysis, the two main predictors of study discontinuation were screening State-Trait Anxiety Inventory (STAI) scores (OR = 1.07 [95%CI = 1.02; 1.12]; p=0.002) and age (OR = 1.06 [95%CI = 1.03; 1.09]; p<0.001). Participants with a family history of dementia (OR = 0.75 [95%CI = 0.55; 1.01]; p=0.063) and APOE ε4 carriers (OR = 0.79 [95%CI = 0.6; 1.04]; p=0.094) were less likely to discontinue from the study, with the association being marginally significant. In these analyses, sex, race and ethnicity, cognitive scores and amyloid/tau PET scores were not associated with study dropout.
CONCLUSIONS: In the A4 trial, older participants and those with higher levels of anxiety at baseline as measured by the STAI were more likely to discontinue while those who had a family history of dementia or were APOE ε4 carriers were less likely to drop out. These findings have direct implications for future preclinical trial design and selection processes to identify those individuals at greatest risk of dropout and provide information to the study team to develop effective selection and retention strategies in AD prevention studies.
CITATION:
R. Raman ; K. Hussen ; M.C. Donohue ; K. Ernstrom ; K.C. Holdridge ; O. Langford ; D.P. Molina-Henry ; A.L. Pierce ; J.R. Sims ; A. Smith ; R. Yaari ; P.S. Aisen ; R. Sperling ; J.D. Grill ; and the A4 Study Team (2024): Pre-Randomization Predictors of Study Discontinuation in a Preclinical Alzheimer’s Disease Randomized Controlled Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.136
LEFT FRONTOPARIETAL CONTROL NETWORK CONNECTIVITY MODERATES THE EFFECT OF AMYLOID ON COGNITIVE DECLINE IN PRECLINICAL ALZHEIMER’S DISEASE: THE A4 STUDY
R. Boyle, H.M. Klinger, Z. Shirzadi, G.T. Coughlan, M. Seto, M.J. Properzi, D.L. Townsend, Z. Yuan, C. Scanlon, R.J. Jutten, K.V. Papp, R.E. Amariglio, D.M. Rentz, J.P. Chhatwal, M.C. Donohue, R.A. Sperling, A.P. Schultz, R.F. Buckley, and on behalf of the A4 Study Team
J Prev Alz Dis 2024;4(11):881-888
Show summaryHide summaryBACKGROUND: Stronger resting-state functional connectivity of the default mode and frontoparietal control networks has been associated with cognitive resilience to Alzheimer’s disease related pathology and neurodegeneration in smaller cohort studies.
OBJECTIVES: We investigated whether these networks are associated with longitudinal CR to AD biomarkers of beta-amyloid (Aβ).
DESIGN: Longitudinal mixed.
SETTING: The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study and its natural history observation arm, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study.
PARTICIPANTS: A sample of 1,021 cognitively unimpaired older adults (mean age = 71.2 years [SD = 4.7 years], 61% women, 42% APOEε4 carriers, 52% Aβ positive).
MEASUREMENTS: Global cognitive performance (Preclinical Alzheimer’s Cognitive Composite) was assessed over an average 5.4 year follow-up period (SD = 2 years). Cortical Aβ and functional connectivity (left and right frontoparietal control and default mode networks) were estimated from fMRI and PET, respectively, at baseline. Covariates included baseline age, APOEε4 carrier status, years of education, adjusted gray matter volume, head motion, study group, cumulative treatment exposure, and cognitive test version.
RESULTS: Mixed effects models revealed that functional connectivity of the left frontoparietal control network moderated the negative effect of Aβ on cognitive change (p = .025) such that stronger connectivity was associated with reduced Aβ-related cognitive decline.
CONCLUSIONS: Our results demonstrate a potential protective effect of functional connectivity in preclinical AD, such that stronger connectivity in this network is associated with slower Aβ-related cognitive decline.
CITATION:
R. Boyle ; H.M. Klinger ; Z. Shirzadi ; G.T. Coughlan ; M. Seto ; M.J. Properzi ; D.L. Townsend ; Z. Yuan ; C. Scanlon ; R.J. Jutten ; K.V. Papp ; R.E. Amariglio ; D.M. Rentz ; J.P. Chhatwal ; M.C. Donohue ; R.A. Sperling ; A.P. Schultz ; R.F. Buckley ; and on behalf of the A4 Study Team ; (2024): Left Frontoparietal Control Network Connectivity Moderates the Effect of Amyloid on Cognitive Decline in Preclinical Alzheimer’s Disease: The A4 Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.140
MAXIMIZING THE UTILITY OF ALZHEIMER’S DISEASE TRIAL DATA: SHARING OF BASELINE A4 AND LEARN DATA
G.A. Jimenez-Maggiora, A.P. Schulz, M.C. Donohue, H. Qiu, S.N. Jaiswal, O. Adegoke, R. Gallardo, O. Baryshnikava, R.A. Rissman, S. Abdel-Latif, R.A. Sperling, P.S. Aisen, for the A4 and LEARN Study Teams
J Prev Alz Dis 2024;4(11):889-894
Show summaryHide summaryBACKGROUND: The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies were conducted between 2014 and 2023, with enrollment completed in 2017 and final study results reported in 2023. The study screening process involved the collection of initial clinical, cognitive, neuroimaging, and genetic measures to determine eligibility. Once randomized, enrolled participants were assessed every four weeks over a 4.5-year follow-up period during which longitudinal clinical, cognitive, and neuroimaging measures were collected. A large number of longitudinal fluid biospecimens were also collected and banked. Consistent with the NIH data sharing policy and the principles of Open Science, the A4/LEARN investigators aimed to share data as broadly and early as possible while still protecting participant privacy and confidentiality and the scientific integrity of the studies.
OBJECTIVES: We describe the approach, methods, and platforms used to share the A4 and LEARN pre-randomization study data for secondary research use. Preliminary results measuring the impact of these efforts are also summarized. We conclude with a discussion of lessons learned and next steps.
DESIGN: The materials shared included de-identified quantitative and image data, analysis software, instruments, and documentation.
SETTING: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan, and Australia.
PARTICIPANTS: The A4 study screened (n=6763), enrolled, and randomized (n=1169) participants between the ages of 65 and 85 with a blinded follow-up period of 240 weeks followed by an open-label period of variable length. The LEARN study screened and enrolled individuals (n=538) who were ineligible for the A4 study based on nonelevated measures of amyloid accumulation using positron emission tomography imaging (amyloid PET).
MEASUREMENTS: We provide descriptive measures of the data shared and summarize the frequency, characteristics, and status of all data access requests submitted to date. We evaluate the scientific impact of the data-sharing effort by conducting a literature search to identify related publications.
RESULTS: The A4 and LEARN pre-randomization study data were released in December 2018. As of May 8, 2024, 1506 requests have been submitted by investigators and citizen scientists from more than 50 countries. We identified 49 peer-reviewed publications that acknowledge the A4/LEARN study.
CONCLUSIONS: Our initial results provide evidence supporting the feasibility and scientific utility of broad and timely sharing of Alzheimer’s disease trial data.
CITATION:
G.A. Jimenez-Maggiora ; A.P. Schulz ; M.C. Donohue ; H. Qiu ; S.N. Jaiswal ; O. Adegoke ; R. Gallardo ; O. Baryshnikava ; R.A. Rissman ; S. Abdel-Latif ; R.A. Sperling ; P.S. Aisen ; for the A4 and LEARN Study Teams (2024): Maximizing the Utility of Alzheimer’s Disease Trial Data: Sharing of Baseline A4 and LEARN Data . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.120
EDITORIAL: ON THE 2024 ALZHEIMER’S ASSOCIATION CRITERIA: STILL NOT READY FOR CLINICAL USE
R.Z. Zhou, A. Wimo, B. Winblad
J Prev Alz Dis 2024;4(11):895-896
Show summaryHide summary
CITATION:
R.Z. Zhou ; A. Wimo ; B. Winblad ; (2024): Editorial: On the 2024 Alzheimer’s Association Criteria: Still Not Ready for Clinical Use. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.141
NOVEL BLOOD-BASED BIOMARKERS AND DISEASE MODIFYING THERAPIES FOR ALZHEIMER’S DISEASE. ARE WE READY FOR THE NEW ERA?
R. Korologou-Linden, J. Kalsi, D. Kafetsouli, A. Olawale, D. Wingfield, D. Mummery, B. Hayhoe, O. Robinson, A. Majeed, L.T. Middleton
J Prev Alz Dis 2024;4(11):897-902
Show summaryHide summaryRecent positive trials for novel disease modifying therapies of anti-amyloid monoclonal antibodies represent a paradigm shift in the prevention and management of Alzheimer’s disease, a relentlessly progressive and debilitating disease of old age. The reported efficacy of these new agents when given early in the disease trajectory is dependent on an early and accurate disease diagnosis, which is currently based on cerebrospinal fluid tests or/and neuro-imaging studies such as positron emission tomography. These confirmatory tests provide in vivo evidence of the pathological signature of Alzheimer’s disease, of increased cerebral amyloid and tau burden and neurodegeneration. The emergence of blood-based biomarkers represents another breakthrough, offering a less invasive and scalable diagnostic tool that could be applied in both primary and specialist care settings, potentially revolutionizing Alzheimer’s disease clinical pathways. However, healthcare systems face challenges in the adoption of these new technologies and therapies due to diagnostic and treatment capacity constraints, as well as financial and infrastructure requirements.
CITATION:
R. Korologou-Linden ; J. Kalsi ; D. Kafetsouli ; A. Olawale ; D. Wingfield ; D. Mummery ; B. Hayhoe ; O. Robinson ; A. Majeed ; L.T. Middleton (2024): Novel Blood-Based Biomarkers and Disease Modifying Therapies for Alzheimer’s Disease. Are We Ready for the New Era?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.83
EXAMINING THE DIAGNOSTIC ACCURACY OF A NOVEL PERFORMANCE-BASED TEST FOR ALZHEIMER’S DISEASE SCREENING
A.M. Reed, K. Duff, L.E. Dibble, S.S. Paul, A. Hooyman, S.Y. Schaefer
J Prev Alz Dis 2024;4(11):903-907
Show summaryHide summaryAffordable, rapid methods for identifying mild Alzheimer’s disease (AD) are needed. A simple, brief performance-based test involving the learning of functional upper-extremity movements has been developed and is associated with AD pathology and functional decline. However, its specificity to AD relative to other neurodegenerative diseases that present with motor impairment is unknown. This study examined whether this novel test could distinguish between 34 participants diagnosed with mild AD (Clinical Dementia Rating Scale = 0.5-1) from 23 participants with mild-to-moderate Parkinson’s disease (PD) (Hoehn & Yahr = 2-3) using Receiver Operating Characteristic analysis of secondary data from two separate clinical trials. Indicators of diagnostic accuracy demonstrated that the test identified participants with AD, who had worse scores than those with PD, suggesting it may be a viable screening tool for mild AD. Exploratory analyses with a control group (n=52) further showed that test scores were not sensitive to motor dysfunction.
CITATION:
A.M. Reed ; K. Duff ; L.E. Dibble ; S.S. Paul ; A. Hooyman ; S.Y. Schaefer (2024): Examining the Diagnostic Accuracy of a Novel Performance-Based Test for Alzheimer’s Disease Screening. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.93
PREDICTING COGNITIVE DECLINE FOR NON-DEMENTED ADULTS WITH HIGH BURDEN OF TAU PATHOLOGY, INDEPENDENT OF AMYLOID STATUS
H.-S. Wu, L. Li, Q.-Q. Sun, C.-C. Tan, L. Tan, W. Xu, for the Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2024;4(11):908-916
Show summaryHide summaryBACKGROUND: Abnormal tau proteins are independent contributors to cognitive impairment. Nevertheless, not all individuals exposed to high-level tau pathology will develop cognitive dysfunction. We aimed to construct a model to predict cognitive trajectory for this high-risk population.
METHOD: Longitudinal data of 181 non-demented adults (mean age= 73.1; female= 45%), who were determined to have high cerebral burden of abnormal tau by cerebrospinal fluid (CSF) measurements of phosphorylated tau (ptau181) or total tau, were derived from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Cognitive decline was defined as Mini-Mental State Examination scores decline ≥ 3 over three years. A predictive nomogram was constructed using stepwise backward regression method. The discrimination, calibration, and clinical usefulness of the nomogram were evaluated. The model was validated in another 189 non-demented adults via a cross-sectional set (n=149, mean age = 73.9, female = 51%) and a longitudinal set (n= 40, mean age = 75, female = 48%). Finally, the relationships of the calculated risk scores with cognitive decline and risk of Alzheimer’s disease were examined during an extended 8-year follow-up.
RESULT: Lower volume of hippocampus (odds ratio [OR] = 0.37, p< 0.001), lower levels of CSF sTREM2 (OR = 0.76, p = 0.003), higher scores of Alzheimer’s Disease Assessment Scale-Cognitive (OR = 1.15, p = 0.001) and Functional Activities Questionnaire (OR = 1.16, p = 0.016), and number of APOE ε4 (OR = 1.88, p = 0.039) were associated with higher risk of cognitive decline independent of the amyloid status and were included in the final model. The nomogram had an area of under curve (AUC) value of 0.91 for training set, 0.93 for cross-sectional validation set, and 0.91 for longitudinal validation set. Over the 8-year follow-up, the high-risk group exhibited faster cognitive decline (p< 0.001) and a higher risk of developing Alzheimer’s dementia (HR= 6.21, 95% CI= 3.61-10.66, p< 0.001 ).
CONCLUSION: APOE ε4 status, brain reserve capability, neuroinflammatory marker, and neuropsychological scores can help predict cognitive decline in non-demented adults with high burden of tau pathology, independent of the presence of amyloid pathology.
CITATION:
H.-S. Wu ; L. Li ; Q.-Q. Sun ; C.-C. Tan ; L. Tan ; W. Xu ; for the Alzheimer’s Disease Neuroimaging Initiative (2024): Predicting Cognitive Decline for Non-Demented Adults with High Burden of Tau Pathology, Independent of Amyloid Status. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.82
NON-GENETIC RISK FACTORS OF ALZHEIMER’S DISEASE: AN UPDATED UMBRELLA REVIEW
S.-Y. He, W.-M. Su, X.-J. Wen, S.-J. Lu, B. Cao, B. Yan, Y.-P. Chen
J Prev Alz Dis 2024;4(11):917-927
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by intricate genetic and environmental etiology. The objective of this study was to identify robust non-genetic risk factors for AD through an updated umbrella review.
METHODS: We conducted a comprehensive search of meta-analyses and systematic reviews on non-genetic risk factors associated with AD in PubMed, Cochrane, Embase, and Ovid Medline up to June 30, 2023. After collecting data, we estimated the summary effect size and their 95% confidence intervals. The degree of heterogeneity between studies was assessed using I2 statistics and a 95% prediction interval was determined. Additionally, we evaluated potential excess significant bias and small study effects within the selected candidate studies.
RESULTS: The umbrella review encompassed a total of 53 eligible papers, which included 84 meta-analyses covering various factors such as lifestyle, diet, environmental exposures, comorbidity or infections, drugs, and biomarkers. Based on the evidence classification criteria employed in this study, two factors as convincing evidence (Class I), including rheumatoid arthritis (RA), potentially reduced the risk of AD, but diabetes significantly increased the risk of AD. Furthermore, three factors as highly suggestive evidence (Class II), namely depression, high homocysteine, and low folic acid level, potentially increased the risk of AD.
CONCLUSION: Our findings highlight several risk factors associated with AD that warrant consideration as potential targets for intervention. However, it is crucial to prioritize the identified modifiable risk factors, namely rheumatoid arthritis, diabetes, depression, elevated homocysteine levels, and low folic acid levels to effectively address this complex neurodegenerative disorder.
CITATION:
S.-Y. He ; W.-M. Su ; X.-J. Wen ; S.-J. Lu ; B. Cao ; B. Yan ; Y.-P. Chen (2024): Non-Genetic Risk Factors of Alzheimer’s Disease: An Updated Umbrella Review. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.100
OPTIMISING ALZHEIMER’S DISEASE DIAGNOSIS AND TREATMENT: ASSESSING COST-UTILITY OF INTEGRATING BLOOD BIOMARKERS IN CLINICAL PRACTICE FOR DISEASEMODIFYING TREATMENT
S. Aye, R. Handels, B. Winblad, L. Jönsson
J Prev Alz Dis 2024;4(11):928-942
Show summaryHide summaryBACKGROUND: Recent developments in blood biomarkers (BBM) have shown promising results in diagnosing amyloid pathology in Alzheimer’s Disease (AD). However, information on how these BBMs can best be used in clinical settings to optimise clinical decision-making and long-term health outcomes for individuals with AD is still lacking.
OBJECTIVES: We aim to assess the potential value of BBM in AD diagnosis within the context of disease-modifying treatment (DMT).
DESIGN: We developed a decision analytic model to evaluate the long-term health outcomes using BBM in AD diagnosis. We compared standard of care (SOC) diagnosis workflow to the integration of BBM as a (1) referral decision tool in primary health center (PHC) and (2) triaging tool for invasive CSF examination in specialist memory clinic (MC). We combined a decision tree and a Markov model to simulate the patient’s diagnostic journey, treatment decisions following diagnosis and long-term health outcomes. Input parameters for the model were identified from published literature and registry data analysis. We conducted a cost-utility analysis from the societal perspective using a one-year cycle length and a 30-year (lifetime) horizon.
MEASUREMENTS: We reported the simulated outcomes in the percentage of correct diagnosis, costs (in 2022 Euros), quality-adjusted life year (QALY), and incremental cost-effectiveness ratios (ICER) associated with each diagnosis strategy.
RESULTS: Compared to SOC, integrating BBM in PHC increased patient referrals by 8% and true positive AD diagnoses by 10.4%. The lifetime costs for individuals diagnosed with AD were € 249,685 and €250,287, and QALYs were 9.5 and 9.52 in SOC and PHC pathways, respectively. The cost increments were €603, and QALYs gained were 0.01, resulting in an ICER of €48,296. Using BBM in MC reduced the exposure to invasive CSF procedures and costs but also reduced true positive AD diagnoses and QALYs.
CONCLUSIONS: Using BBM at PHC to make referral decisions might increase initial diagnostic costs but can prevent high costs associated with disease progression, providing a cost-effective DMT is available, whereas using BBM in MC could reduce the initial evaluation cost but incur high costs associated with disease progression.
CITATION:
S. Aye ; R. Handels ; B. Winblad ; L. Jönsson (2024): Optimising Alzheimer’s Disease Diagnosis and Treatment: Assessing Cost-Utility of Integrating Blood Biomarkers in Clinical Practice for Disease-Modifying Treatment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.67
PREDICTING BRAIN AMYLOID STATUS USING THE NATIONAL INSTITUTE OF HEALTH TOOLBOX (NIHTB) FOR ASSESSMENT OF NEUROLOGICAL AND BEHAVIORAL FUNCTION
Y. Cheng, E. Ho, S. Weintraub, D. Rentz, R. Gershon, S. Das, H.H. Dodge
J Prev Alz Dis 2024;4(11):943-957
Show summaryHide summaryBACKGROUND: Amyloid-beta (Aβ) plaque is a neuropathological hallmark of Alzheimer’s disease (AD). As anti-amyloid monoclonal antibodies enter the market, predicting brain amyloid status is critical to determine treatment eligibility.
OBJECTIVE: To predict brain amyloid status utilizing machine learning approaches in the Advancing Reliable Measurement in Alzheimer’s Disease and Cognitive Aging (ARMADA) study.
DESIGN: ARMADA is a multisite study that implemented the National Institute of Health Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) in older adults with different cognitive ability levels (normal, mild cognitive impairment, early-stage dementia of the AD type).
SETTING: Participants across various sites were involved in the ARMADA study for validating the NIHTB.
PARTICIPANTS: 199 ARMADA participants had either PET or CSF information (mean age 76.3 ± 7.7, 51.3% women, 42.3% some or complete college education, 50.3% graduate education, 88.9% White, 33.2% with positive AD biomarkers).
MEASUREMENTS: We used cognition, emotion, motor, sensation scores from NIHTB, and demographics to predict amyloid status measured by PET or CSF. We applied LASSO and random forest models and used the area under the receiver operating curve (AUROC) to evaluate the ability to identify amyloid positivity.
RESULTS: The random forest model reached AUROC of 0.74 with higher specificity than sensitivity (AUROC 95% CI:0.73 – 0.76, Sensitivity 0.50, Specificity 0.88) on the held-out test set; higher than the LASSO model (0.68 (95% CI:0.68 – 0.69)). The 10 features with the highest importance from the random forest model are: picture sequence memory, cognition total composite, cognition fluid composite, list sorting working memory, words-in-noise test (hearing), pattern comparison processing speed, odor identification, 2-minutes-walk endurance, 4-meter walk gait speed, and picture vocabulary. Overall, our model revealed the validity of measurements in cognition, motor, and sensation domains, in associating with AD biomarkers.
CONCLUSION: Our results support the utilization of the NIH toolbox as an efficient and standardizable AD biomarker measurement that is better at identifying amyloid negative (i.e., high specificity) than positive cases (i.e., low sensitivity).
CITATION:
Y. Cheng ; E. Ho ; S. Weintraub ; D. Rentz ; R. Gershon ; S. Das ; H.H. Dodge (2024): Predicting Brain Amyloid Status Using the National Institute of Health Toolbox (NIHTB) for Assessment of Neurological and Behavioral Function . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.77
VALUE OF KNOWING: HEALTH-RELATED BEHAVIOR CHANGES FOLLOWING AMYLOID PET RESULTS DISCLOSURE IN MILD COGNITIVE IMPAIRMENT
Y. Wang, D. Ren, J.S. Roberts, L.K. Tamres, J.H. Lingler
J Prev Alz Dis 2024;4(11):958-965
Show summaryHide summaryBACKGROUND: Growing evidence supports the clinical utility of amyloid PET, however, whether patients at risk for dementia use knowledge of their brain amyloid status to alter their health behaviors remains unclear.
OBJECTIVES: To explore the effect of amyloid PET results disclosure on self-reported health behaviors in patients with mild cognitive impairment.
DESIGN: Self-reported health behaviors were a secondary outcome of the Return of Amyloid Imaging Scan Results (RAISR) randomized clinical trial of amyloid PET results disclosure for individuals with mild cognitive impairment.
SETTING: Academic medical center.
PARTICIPANTS: RAISR study participants included 82 patients with mild cognitive impairment who were 92% non-Hispanic white, 59% male, and, on average, 73 ± 8.61 years old with 16.25 ± 2.49 years of education.
INTERVENTION: Participants were assigned to a scan group with the opportunity to have an amyloid PET scan and learn their results or to a control group consisting only of a mild cognitive impairment education session and no opportunity for an amyloid PET scan.
MEASUREMENTS: A 14-item health behavior questionnaire supplemented with qualitative data from the open-ended text entries to describe “other” health behaviors and follow-up semi-structured interviews. Baseline assessments were conducted prior to group assignment. For the present analysis, 71 participants had available data and scan group participants were divided by amyloid status, creating three groups for comparison: amyloid positive, amyloid negative, and control (no scan).
RESULTS: Over 12 months of follow-up, no significant differences were observed in lifestyle, vitamin/supplement use, stress reduction activities, cognitive stimulation, or advance directive completion. Amyloid-negative participants were less likely than controls to consider long-term care insurance (63.6% vs. 89.2%; P = .025), and to endorse behaviors classified as “other” (36.4% vs. 64.9%; P = 0.037). After adjusting for education level, gender, and Mini-Mental State Exam score, logistic regression showed that amyloid-negative patients were 74% less likely than controls to report “other” behaviors (OR = 0.26, 95% CI [0.08, 0.85], P = 0.025), and 78% less likely to consider long-term care insurance (OR= 0.22, 95% CI [0.06, 0.86], P = 0.03). Qualitative analysis of open-ended questionnaire data and supplemental interviews with scan group participants revealed “other” activities to include changes in areas like employment, driving, and residential status, and engagement in other non-medical activities (e.g., pursuing bucket lists).
CONCLUSIONS: This exploratory analysis of health-related behavior changes following amyloid PET disclosure suggests that the value of knowing one’s brain amyloid status may differ by scan result and encompass actions that focus more on maximizing quality of life than promoting cognitive health.
CITATION:
Y. Wang ; D. Ren ; J.S. Roberts ; L.K. Tamres ; J.H. Lingler ; (2024): Value of Knowing: Health-Related Behavior Changes following Amyloid PET Results Disclosure in Mild Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.50
LONGITUDINAL EVOLUTION OF FINANCIAL CAPACITY AND CEREBRAL TAU AND AMYLOID BURDEN IN OLDER ADULTS WITH NORMAL COGNITION OR MILD COGNITIVE IMPAIRMENT
K.J. Mimmack, E.H. Sprague, R.E. Amariglio, P. Vannini, G.A. Marshall, for the Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2024;4(11):966-974
Show summaryHide summaryBackground: Declining ability to independently perform instrumental activities of daily living (IADL) is a hallmark of early-stage Alzheimer’s disease (AD). Financial capacity, an aspect of IADL, includes financial skills such as balancing a checkbook and making change and is potentially sensitive to early decline in cognitive abilities, raising the question of how financial capacity is affected by buildup of cerebral tau and amyloid—hallmarks of AD pathology.
Objectives: This study aimed to examine the relationship between cerebral tau, amyloid, and their interaction with change in financial capacity over time.
Design: Participants were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to have at least one yearly follow-up Financial Capacity Instrument–Short Form (FCI-SF) exam and a flortaucipir (tau) PET scan within 6 months of baseline (and in a subset, a florbetapir (amyloid) PET scan within a year of baseline).
Setting: Multi-center international cohort study.
Participants: Sample size was 507—322 cognitively normal (CN) and 185 with amnestic mild cognitive impairment (MCI). Sixty-two percent (N=316) had amyloid data.
Measurements: Linear mixed-effects models predicted FCI-SF total score from baseline tau, age, gender, premorbid intelligence, executive function, memory, and the interaction of each with time. Regions of interest included inferior temporal, entorhinal cortex, precuneus, posterior cingulate, supramarginal, and dorsolateral prefrontal (DLPF). Additional models examined amyloid and its interaction with tau. Results were adjusted for multiple comparisons.
Results: Among the whole sample and in CN participants alone, higher baseline tau in all regions, most prominently in the inferior temporal, entorhinal cortex, and supramarginal regions, was significantly associated with worse performance on the FCI-SF over time. Among MCI participants alone, this relationship was significant in the entorhinal cortex (unstandardized b = 0.27, t = 3.71, adjusted p = 0.001), inferior temporal (b = 0.27, t = 3.96, p < 0.001), precuneus (b = 0.27, t = 3.04, p = 0.01), and supramarginal (b = 0.27, t = 2.74, p = 0.02) regions. Amyloid alone was significantly associated with worse FCI-SF performance in only the whole sample (b = 0.15, t = 2.37, p = 0.04), and a three-way interaction between tau, amyloid, and time was only present for entorhinal cortex tau in CN individuals (b = -1.61, t = -2.61, p = 0.03).
Conclusions: Early tau accumulation is linked to worsening financial capacity over time in CN older adults and MCI. Declining financial capacity may signal pathological buildup and serve as an early warning sign for AD, and future research should continue to investigate the longitudinal relationship between tau, financial capacity, and other IADL.
CITATION:
K.J. Mimmack ; E.H. Sprague ; R.E. Amariglio ; P. Vannini ; G.A. Marshall ; for the Alzheimer’s Disease Neuroimaging Initiative (2023): Longitudinal Evolution of Financial Capacity and Cerebral Tau and Amyloid Burden in Older Adults with Normal Cognition or Mild Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.121
SAFETY, EFFICACY AND CLINICAL APPLICATIONS OF FOCUSED ULTRASOUND-MEDIATED BLOOD BRAIN BARRIER OPENING IN ALZHEIMER’S DISEASE: A SYSTEMATIC REVIEW
A. Patwardhan, T. Wilkinson, Y. Meng, I. Alhashyan, S.E. Black, N. Lipsman, M. Masellis
J Prev Alz Dis 2024;4(11):975-982
Show summaryHide summaryAlzheimer’s disease is a neurodegenerative disorder marked by cognitive decline and brain pathology involving amyloid plaques and neurofibrillary tangles. Current drug development focuses on disease-modifying therapies, primarily antibodies targeting amyloid or tau. However, the blood-brain barrier (BBB) poses a challenge for drug delivery to the brain. Pre- and early clinical data suggests that Focused Ultrasound (FUS) technology safely enhances BBB permeability without damaging brain tissue, enabling drug delivery. This systematic review discusses the application of FUS to open the BBB for the treatment of Alzheimer’s disease (AD). We review the safety, efficacy, and potential biological effects of FUS-mediated BBB opening in AD patients.
CITATION:
A. Patwardhan ; T. Wilkinson ; Y. Meng ; I. Alhashyan ; S.E. Black ; N. Lipsman ; M. Masellis (2024): Safety, Efficacy and Clinical Applications of Focused Ultrasound-Mediated Blood Brain Barrier Opening in Alzheimer’s Disease: A Systematic Review. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.85
ECONOMIC IMPACT OF PROGRESSION FROM MILD COGNITIVE IMPAIRMENT TO ALZHEIMER DISEASE IN THE UNITED STATES
F.H. Frech, G. Li, T. Juday, Y. Ding, S. Mattke, A. Khachaturian, A.S. Rosenberg, C. Ndiba-Markey, A. Rava, R. Batrla, S. De Santi, H. Hampel
J Prev Alz Dis 2024;4(11):983-991
Show summaryHide summaryBACKGROUND: Limited evidence exists on the economic burden of individuals who progress from mild cognitive impairment (MCI) to Alzheimer disease and related dementia disorders (ADRD).
OBJECTIVES: To assess the all-cause health care resource utilization and costs for individuals who develop ADRD following an MCI diagnosis compared to those with stable MCI.
DESIGN: This was a retrospective cohort study from January 01, 2014, to December 31, 2019.
SETTING: The Merative MarketScan Commercial and Medicare Databases were used.
PARTICIPANTS: Individuals were included if they: (1) were aged 50 years or older; (2) had ≥1 claim with an MCI diagnosis based on the International Classification of Diseases, Ninth Revision (ICD-9) code of 331.83 or the Tenth Revision (ICD-10) code of G31.84; and had continuous enrollment. Individuals were excluded if they had a diagnosis of Parkinson’s disease or ADRD or prescription of ADRD medication.
MEASUREMENTS: Outcomes included all-cause utilization and costs per patient per year in the first 12 months following MCI diagnosis, in total and by care setting: inpatient admissions, emergency department (ED) visits, outpatient visits, and pharmacy claims.
RESULTS: Out of the total of 5185 included individuals, 1962 (37.8%) progressed to ADRD (MCI-to-ADRD subgroup) and 3223 (62.2%) did not (Stable MCI subgroup). Adjusted all-cause utilization was higher for all care settings in the MCI-to-ADRD subgroup compared with the Stable MCI subgroup. Adjusted all-cause mean total costs ($34 599 vs $24 541; mean ratio [MR], 1.41 [95% CI, 1.31-1.51]; P<.001), inpatient costs ($47 463 vs $38 004; MR, 1.25 [95% CI, 1.08-1.44]; P=.002), ED costs ($4875 vs $3863; MR, 1.26 [95% CI, 1.11-1.43]; P<.001), and outpatient costs ($16 652 vs $13 015; MR, 1.28 [95% CI, 1.20-1.37]; P<.001) were all significantly higher for the MCI-to-ADRD subgroup compared with the Stable MCI subgroup.
CONCLUSIONS: Individuals who progressed from MCI to ADRD had significantly higher health care costs than individuals with stable MCI. Early identification of MCI and delaying its progression is important to improve patient and economic outcomes.
CITATION:
F.H. Frech ; G. Li ; T. Juday ; Y. Ding ; S. Mattke ; A. Khachaturian ; A.S. Rosenberg ; C. Ndiba-Markey ; A. Rava ; R. Batrla ; S. De Santi ; H. Hampel (2024): Economic Impact of Progression from Mild Cognitive Impairment to Alzheimer Disease in the United States. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.68
EVALUATION OF CLINICAL MEANINGFULNESS OF FORTASYN CONNECT IN TERMS OF “TIME SAVED”
S.P. Dickson, A. Solomon, M. Kivipelto, T. Hartmann, A.M.J. van Hees, A. Brownlee, B. Haaland, C.H. Mallinckrodt, S.B. Hendrix
J Prev Alz Dis 2024;4(11):992-997
Show summaryHide summaryAssessment of meaningfulness in randomized clinical trials (RCTs) in Alzheimer’s disease (AD) is challenging, particularly in early disease. Converting clinical outcomes to disease progression time allows assessment of treatment effects using a metric that is understandable and meaningful: time. We demonstrate time savings assessments using meta time component tests (TCTs) in the LipiDiDiet multinutrient RCT. Dietary patterns are important for dementia prevention, likely due to individual cumulative nutrient effects. LipiDiDiet used a multinutrient (Fortasyn Connect) formulation in patients with prodromal AD, benefitting cognition (5-item composite NTB, effect 0.089), cognition and function (CDR-SB, -0.605), and slowing hippocampal atrophy (0.122 cm3). Meaningfulness of point differences is unclear. However, a combination TCT showed 9-month disease time savings at 24 months (38% slowing of disease time): 9.0, 10.5, and 7.2 months for NTB, CDR-SB, and hippocampal volume, underscoring the value of TCTs in AD RCTs and the need for continued validation of this approach.
CITATION:
S.P. Dickson ; A. Solomon ; M. Kivipelto ; T. Hartmann ; A.M.J. van Hees ; A. Brownlee ; B. Haaland ; C.H. Mallinckrodt ; S.B. Hendrix ; (2024): Evaluation of Clinical Meaningfulness of Fortasyn Connect in Terms of “Time Saved”. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.55
EFFECTIVENESS OF RESISTANCE EXERCISE ON COGNITIVE FUNCTION IN ANIMAL MODELS OF ALZHEIMER DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS
F.O. de Andrade Santos, A.A. Passos, R.M. Arida, L. Teixeira-Machado
J Prev Alz Dis 2024;4(11):998-1012
Show summaryHide summaryAIM: Alzheimer’s disease (AD) is among common cause of dementia. Complementary therapies, such as resistance exercise (RE), have been proposed as an alternative for the treatment of AD. We performed a systematic review and meta-analysis to investigate the effects of RE on the cognitive function of AD animal models and their physiological mechanisms.
METHODS: This review was submitted to PROSPERO (CRD42019131266) and was done according to PRISMA checklist. Four databases were used in the search: MEDLINE/PUBMED, SCOPUS, Web of Science and Google Scholar. We used SYRCLE and CAMAREDES to assess the risk of bias and methodological quality. We calculated the standardized mean difference using 95% confidence intervals and considered the random effects model and p < 0.05 to determine significance.
KEY FINDINGS: A total of 1,807 studies were founded, and after the selection process, only 11 studies were included in this review and 8 studies were included for meta-analysis. Four studies applied RE before AD induction, 7 studies applied RE after AD induction or in the AD condition. All studies included 550 adult and older animals weighing 25-280g. Our analysis revealed that RE had a positive effect on memory in AD animal models but did not show a significant impact on anxiety.
CONCLUSION: RE performed four or six weeks, more than three days a week, had a significant protective effect on memory. The included studies had a high risk of bias and moderate methodological quality. Therefore, RE can be a potential strategy for preventing cognitive decline in animal models.
CITATION:
F.O. de Andrade Santos ; A.A. Passos ; R.M. Arida ; L. Teixeira-Machado (2024): Effectiveness of Resistance Exercise on Cognitive Function in Animal Models of Alzheimer Disease: A Systematic Review and Meta-Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.75
GLOBAL BURDEN OF DEMENTIA DEATH FROM 1990 TO 2019, WITH PROJECTIONS TO 2050: AN ANALYSIS OF 2019 GLOBAL BURDEN OF DISEASE STUDY
Z. Li, N. Yang, L. He, J. Wang, Y. Yang, F. Ping, L. Xu, H. Zhang, W. Li, Y. Li
J Prev Alz Dis 2024;4(11):1013-1021
Show summaryHide summaryBACKGROUND: Dementia is a growing global health challenge. Quantifying the current burden and predicting the future increases of dementia-related deaths are necessary to enhance effective policy decisions and health system planning.
METHODS: Data on dementia mortality was derived from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 study. The 2020-2050 dementia-related deaths were forecasted using the Bayesian age-period-cohort model.
RESULTS: Globally, the number of dementia-related death increased from 0.56 million in 1990 to 1.62 million in 2019 and were estimated to increase to 4.91 million by the year 2050. Metabolic risk factors would become the most important modifiable risk factors affecting dementia death which account for 28.10% of dementia related death by the year 2050. For different Socio-demographic Index (SDI) regions, the low SDI region would have the highest age-standardized mortality rate (ASMR) (29.16 per 100,000) by 2050. Moreover, the number of dementia-related deaths under the age of 70 years was predicted to reach 0.18 million by 2050.
CONCLUSIONS: Dementia related death remains a global health problem, and health policies targeting metabolic risk factors may be an important way to alleviate this problem.
CITATION:
Z. Li ; N. Yang ; L. He ; J. Wang ; Y. Yang ; F. Ping ; L. Xu ; H. Zhang ; W. Li ; Y. Li ; (2024): Global Burden of Dementia Death from 1990 to 2019, with Projections to 2050: An Analysis of 2019 Global Burden of Disease Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.21
ESTIMATED INVESTMENT NEED TO INCREASE ENGLAND’S CAPACITY TO DIAGNOSE ELIGIBILITY FOR AN ALZHEIMER’S TREATMENT TO G7 AVERAGE CAPACITY LEVELS
S. Mattke, Z. Shi, M. Hanson, S. Mitchell, C. Lynch, K. MacLean Kalonji, L. Lanman
J Prev Alz Dis 2024;4(11):1022-1029
Show summaryHide summaryBACKGROUND: As disease-modifying Alzheimer’s (AD) treatments are becoming available, concerns have been raised that even high-income countries lack the diagnostic capacity to accurately identify eligible patients in a timely manner.
OBJECTIVES: We analyze how much NHS England would have to invest in capacity for AD specialists, biomarker testing with PET scans or CSF testing and MRI scans to reach G7 average levels and estimate the effect on wait times in the diagnostic process.
DESIGN: Desk research and expert interviews for cost and capacity data. Markov model to estimate wait times.
SETTING: NHS England.
MEASUREMENTS: AD specialists, and PET and MRI scanners per capita in G7 countries and wait times in England under different investment scenarios.
RESULTS: England has the lowest number of PET and MRI scanners and the second-lowest of AD specialists per capita among the G7 countries. An investment of GBP 14 billion over ten years would be needed to reach G7 average levels, of which 31%, 22%, 10%, 37% would be devoted to capacity for memory assessment services, PET scanning, CSF analysis, and MRI scanning, respectively. This investment would reduce estimated average wait times by around 87% between 2023 and 2032.
CONCLUSIONS: The NHS England has large gaps in diagnostic capacity for AD. Without substantial investments, AD patients in England would experience substantial wait times and avoidable disease progression.
CITATION:
S. Mattke ; Z. Shi ; M. Hanson ; S. Mitchell ; C. Lynch ; K. MacLean Kalonji ; L. Lanman ; (2024): Estimated Investment Need to Increase England’s Capacity to Diagnose Eligibility for an Alzheimer’s Treatment to G7 Average Capacity Levels. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.24
“BACK TO BRAAK”: ROLE OF NUCLEUS REUNIENS AND SUBCORTICAL PATHWAYS IN ALZHEIMER’S DISEASE PROGRESSION
S. Censi, C. Sestieri, M. Punzi, A. Delli Pizzi, A. Ferretti, F. Gambi, V. Tomassini, S. Delli Pizzi, S.L. Sensi, for the Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2024;4(11):1030-1040
Show summaryHide summaryBACKGROUND: Patients with Alzheimer’s Disease (AD) exhibit structural alterations of the thalamus that correlate with clinical symptoms. However, given the anatomical complexity of this brain structure, it is still unclear whether atrophy affects specific thalamic nuclei and modulates the clinical progression from a prodromal stage, known as Mild Cognitive Impairment (MCI), to full-fledged AD.
OBJECTIVES: To characterize the structural integrity of distinct thalamic nuclei across the AD spectrum, testing whether MCI patients who convert to AD (c-MCI) show a distinctive pattern of thalamic structural alterations compared to patients who remain stable (s-MCI).
DESIGN: Investigating between-group differences in the volumetric features of distinct thalamic nuclei across the AD spectrum.
SETTING: Prodromal and clinical stages of AD.
PARTICIPANTS: We analyzed data from 84 healthy control subjects (HC), 58 individuals with MCI, and 102 AD patients. The dataset was obtained from the AD Neuroimaging Initiative (ADNI-3) database. The MCI group was further divided into two subgroups depending on whether patients remained stable (s-MCI, n=22) or progressed to AD (s-MCI, n=36) in the 48 months following the diagnosis.
MEASUREMENTS: A multivariate analysis of variance (MANOVA) assessed group differences in the volumetric features of distinct thalamic nuclei obtained from magnetic resonance (MR) images. A stepwise discriminant function analysis identified which feature most effectively predicted the conversion to AD. The corresponding predictive performance was evaluated through a Receiver Operating Characteristic approach.
RESULTS: AD and c-MCI patients showed generalized atrophy of thalamic nuclei compared to HC. In contrast, no significant structural differences were observed between s-MCI and HC subjects. Compared to s-MCI, c-MCI individuals displayed significant atrophy of the nucleus reuniens and a trend toward significant atrophy in the anteroventral and laterodorsal nuclei. The discriminant function analysis confirmed the nucleus reuniens as a significant predictor of AD conversion, with a sensitivity of 0.73 and a specificity of 0.69.
CONCLUSIONS: In line with the pathophysiological relevance of the nucleus reuniens proposed by seminal post-mortem studies on patients with AD, we confirm the pivotal role of this nucleus as a critical hub in the clinical progression to AD. We also propose a theoretical model to explain the evolving dysfunction of subcortical brain networks in the disease process.
CITATION:
S. Censi ; C. Sestieri ; M. Punzi ; A. Delli Pizzi ; A. Ferretti ; F. Gambi ; V. Tomassini ; S. Delli Pizzi ; S.L. Sensi ; for the Alzheimer’s Disease Neuroimaging Initiative (2024): “Back to Braak”: Role of Nucleus Reuniens and Subcortical Pathways in Alzheimer’s Disease Progression. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.42
MAGNETIC RESONANCE IMAGING-NEGATIVE CEREBRAL AMYLOID ANGIOPATHY: CEREBROSPINAL FLUID AMYLOID-Β42 OVER AMYLOID POSITRON EMISSION TOMOGRAPHY
J.-M. Pyun, M.J. Kang, S.J. Baek, K. Lee, Y.H. Park, S.Y. Kim, for the Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2024;4(11):1041-1046
Show summaryHide summaryBACKGROUND: Cerebral amyloid angiopathy (CAA) pathology is becoming increasingly important in Alzheimer’s disease (AD) because of its potential link to amyloid-related imaging abnormalities, a critical side effect observed during AD immunotherapy. Identification of CAA without typical magnetic resonance imaging (MRI) markers (MRI-negative CAA) is challenging, and novel detection biomarkers are needed.
METHODS: We included 69 participants with high neuritic plaques (NP) burden, with and without CAA pathology (NP with CAA vs. NP without CAA) based on autopsy data from the Alzheimer’s Disease Neuroimaging Initiative. Two participants with hemorrhagic CAA markers based on MRI were excluded and the final analysis involved 36 NP without CAA and 31 NP with CAA. A logistic regression model was used to compare the cerebrospinal fluid (CSF) amyloid-β42 (Aβ42), phosphorylated tau181, and total tau levels, the amyloid positron emission tomography (PET) standardized uptake ratio (SUVR), and cognitive profiles between NP with and without CAA. Regression models for CSF and PET were adjusted for age at death, sex, and the last assessed clinical dementia rating sum of boxes score. Models for cognitive performances was adjusted for age at death, sex, and education level.
RESULTS: NP with CAA had significantly lower CSF Aβ42 levels when compared with those without CAA (110.5 pg/mL vs. 134.5 pg/mL, p-value = 0.002). Logistic regression analysis revealed that low CSF Aβ42 levels were significantly associated with NP with CAA (odds ratio [OR]: 0.957, 95% confidence interval [CI]: 0.928, 0.987, p-value = 0.005). However, amyloid PET SUVR did not differ between NP with CAA and those without CAA (1.39 vs. 1.48, p-value = 0.666). Logistic regression model analysis did not reveal an association between amyloid PET SUVR and NP with CAA (OR: 0.360, 95% CI: 0.007, 1.741, p-value = 0.606).
CONCLUSIONS: CSF Aβ42 is more sensitive to predict MRI-negative CAA in high NP burden than amyloid PET.
CITATION:
J.-M. Pyun ; M.J. Kang ; S.J. Baek ; K. Lee ; Y.H. Park ; S.Y. Kim ; for the Alzheimer’s Disease Neuroimaging Initiative ; (2024): Magnetic Resonance Imaging-Negative Cerebral Amyloid Angiopathy: Cerebrospinal Fluid Amyloid-β42 over Amyloid Positron Emission Tomography. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.49
ASSOCIATION BETWEEN COMORBIDITY INDICES AND FUNCTIONAL AUTONOMY IN INDIVIDUALS WITH COGNITIVE IMPAIRMENT: A SYSTEMATIC REVIEW
M.N. Temedda, A. Garnier-Crussard, C. Mouchoux, V. Dauphinot
J Prev Alz Dis 2024;4(11):1047-1054
Show summaryHide summaryThis systematic review aimed to examine whether higher comorbidity burden, as assessed by comorbidity indices, was associated with a functional autonomy decline in individuals with cognitive impairment. The search was conducted in the following databases: PubMed/MEDLINE, ScienceDirect, Cochrane, and Embase. Both cross-sectional and longitudinal studies that examined the relationship between comorbidity indices and scales measuring activities of daily living (ADL) in individuals with cognitive impairment were included. The quality assessment tool for observational cohort and cross-sectional studies of the National Institutes of Health (NIH) was used. Overall, 12 studies were included, among which three were longitudinal. Significant association was frequently reported by cross-sectional designs (n=7 studies) and only one study reported a significant longitudinal association. This longitudinal study repeatedly assessed both comorbidity burden and functional autonomy, and considered comorbidity burden as a time-varying covariate. Considering comorbidity burden as a time varying covariate may deal with the dynamic nature of comorbidity burden over time, and conducting repeated assessments during the follow-up using both comorbidity index and ADL scales may increase their sensitivity to reliably measure comorbidity burden and functional autonomy decline over time. In conclusion, a higher comorbidity index was associated with a lower level of functional autonomy in people with cognitive impairment. This relationship seems to be dynamic over time and using comorbidity indices and ADL scales only once may not deal with the fluctuation of both comorbidity burden and functional autonomy decline. To cope with complexity of this relationship this review highlights some methodological approaches to be considered.
CITATION:
M.N. Temedda ; A. Garnier-Crussard ; C. Mouchoux ; V. Dauphinot (2024): Association between Comorbidity Indices and Functional Autonomy in Individuals with Cognitive Impairment: A Systematic Review. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.51
PREDICTION OF ALZHEIMER’S DISEASE BASED ON 3D GENOME SELECTED CIRCRNA
R. Chi, K. Li, K. Su, L. Liu, M. Feng, X. Zhang, J. Wang, X. Li, G. He, Y. Shi
J Prev Alz Dis 2024;4(11):1055-1062
Show summaryHide summaryAlzheimer’s disease (AD) is a neurodegenerative disease and there is by far no effective treatment for it, especially in its late stage. Circular RNAs (circRNAs), known as a class of non-coding RNAs are widely observed in eukaryotic transcriptomes, and are reported to play an important role in neurodegenerative diseases including AD. circRNAs usually act as microRNA (miRNA) inhibitors or «sponges» to regulate the function of miRNAs, leading to subsequent changes in protein activities and functions. Accumulating evidence indicates that circRNAs can serve as potential biomarker in AD early prediction. The functional roles of circRNAs are very versatile including miRNAs binding - thus affecting downstream gene expression, generating abnormally translated protein peptides, and affecting epigenetic modifications which subsequently affect AD related gene expressions. Therefore, identifying AD-related circRNAs can contribute to AD early diagnosis and intervention. In this work, we collected and curated an AD-related circRNA dataset; by exploring the circRNAs’ corresponding DNA loci distribution in chromatin 3D conformation (3D genome) and utilize the such 3D genome information, we were able to selected a concise yet predictively effective circRNA panel, based on which, significantly better AD prediction machine learning models were achieved.
CITATION:
R. Chi ; K. Li ; K. Su ; L. Liu ; M. Feng ; X. Zhang ; J. Wang ; X. Li ; G. He ; Y. Shi ; (2024): Prediction of Alzheimer’s Disease Based on 3D Genome Selected circRNA. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.52
FEMALE REPRODUCTIVE FACTORS AND RISK OF MILD COGNITIVE IMPAIRMENT AND DEMENTIA: THE HUNT STUDY
Y. Wedatilake, C. Myrstad, S.E. Tom, B.H. Strand, S. Bergh, G. Selbæk
J Prev Alz Dis 2024;4(11):1063-1072
Show summaryHide summaryBACKGROUND: More women are living with dementia than men worldwide and there is a need to investigate causes for this female preponderance. While reproductive factors have been investigated as risk factors, the results are conflicting. We aim to clarify this using a large cohort with a long observation time, adjusting for multiple health and lifestyle variables and encompassing a wider range of cognitive impairment.
OBJECTIVE: To study the association between menopause age, menarche age and risk of and risk of mild cognitive impairment (MCI) and dementia.
SETTING: The Trøndelag Health study (HUNT), a longitudinal population health study in Norway (1984-2019).
Participants: Women who were ≥70 years in 2017-2019 were assessed for cognitive impairment.
MEASUREMENTS: Data on menopause age and menarche age were obtained from questionnaires. Diagnosis of MCI or dementia was set using a standardised procedure by a diagnostic group of nine physicians. Multinomial logistic regression was used to study the association between menopause age, menarche age and risk of MCI and dementia with adjustment for birth year, education, smoking, ApoE4, number of children, diabetes, body mass index, alcohol use and physical inactivity.
RESULTS: We evaluated 5314 women where 900 (16.9%) had dementia, and 1747 (32.8%) had MCI. Multiple adjusted relative risk ratio (RRR) and 95% confidence intervals (CI) for dementia were: 0.96(95%CI 0.95-0.98) (p<0.001) for menopause age, 0.97(95%CI 0.94-0.99) (p=0.007) for natural menopause age (excluding hysterectomy and/or oophorectomy<55 years) and 0.97(95%CI 0.95-0.99) (p<0.001) for reproductive span (menopause age minus menarche age). Menopause age <45years was associated with a 56% higher risk compared to mean menopause age 50 years. We found no significant associations between menarche age and dementia and no associations with MCI.
CONCLUSIONS: Older menopause age and longer reproductive span corresponding to longer oestrogen exposure were associated with a lower dementia risk. Future studies should explore therapeutical options to offset this risk in women.
CITATION:
Y. Wedatilake ; C. Myrstad ; S.E. Tom ; B.H. Strand ; S. Bergh ; G. Selbæk (2024): Female Reproductive Factors and Risk of Mild Cognitive Impairment and Dementia: The HUNT Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.46
PERFORMANCE OF FULLY-AUTOMATED HIGH-THROUGHPUT PLASMA BIOMARKER ASSAYS FOR ALZHEIMER’S DISEASE IN AMNESTIC MILD COGNITIVE IMPAIRMENT SUBJECTS
G.M. Giuffrè, D. Quaranta, M.G. Vita, E.M. Costantini, S. Citro, C. Carrozza, G. De Ninno, P. Calabresi, C. Marra
J Prev Alz Dis 2024;4(11):1073-1078
Show summaryHide summaryINTRODUCTION: Novel plasma biomarkers are promising for identifying Alzheimer’s disease (AD) pathological processes in vivo, but most currently employed assays have limitations precluding widespread use.
METHODS: CSF and plasma samples were collected from seventy amnestic mild cognitive impairment (aMCI) subjects, stratified as A+ and A-. CSF Aβ40, Aβ42, p-tau181 and t-tau and plasma Aβ40, Aβ42 and p-tau181 quantification were conducted using the Lumipulse G assays (Fujirebio), to evaluate the diagnostic performance of plasma biomarkers and assess their associations with CSF biomarkers.
RESULTS: All plasma biomarkers except Aβ40 showed a very good accuracy in distinguishing A+ aMCI from A- aMCI, Aβ42/p-tau181 ratio being the most accurate (AUC 0.895, sensitivity 95.1%, specificity 82.8%). Plasma biomarkers levels were significantly associated with CSF biomarkers concentration.
DISCUSSION: High-throughput and fully-automated plasma assays could be helpful in discriminating with high accuracy between aMCI in the AD continuum and aMCI unlikely due to AD in clinical settings.
CITATION:
G.M. Giuffrè ; D. Quaranta ; M.G. Vita ; E.M. Costantini ; S. Citro ; C. Carrozza ; G. De Ninno ; P. Calabresi ; C. Marra (2024): Performance of Fully-Automated High-Throughput Plasma Biomarker Assays for Alzheimer’s Disease in Amnestic Mild Cognitive Impairment Subjects. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.58
INTEREST IN AND EXPERIENCE WITH GENETIC TESTING FOR LATE-ONSET MEDICAL CONDITIONS: RESULTS FROM THE NATIONAL POLL ON HEALTHY AGING
S.J. Feldman, D. Blasco, M. Mones, J. Scott Roberts
J Prev Alz Dis 2024;4(11):1079-1086
Show summaryHide summaryBACKGROUND: The increasing availability of genetic testing for late-onset diseases such as Alzheimer’s disease necessitates understanding public perceptions and experiences of such testing among at-risk populations.
OBJECTIVES: To assess (a) prior uptake of genetic testing (both in medical and direct-to-consumer settings), (b) future interest in genetic testing for late-onset conditions (e.g., Alzheimer’s disease, Parkinson’s disease), and (c) perceptions of testing pros and cons among middle-to-older aged adults.
DESIGN: Online, cross-sectional survey study.
SETTING: The National Poll on Healthy Aging at the University of Michigan is a recurring biannual survey of a nationally representative sample of adults aged 50-80. This study reports on a March 2018 fielding of the survey that included a genetic testing module administered to adults aged 50-64.
PARTICIPANTS: Study participants were 991 community-dwelling adults aged 50-64.
MEASUREMENTS: Survey measures assessed (a) prior use of genetic testing, (b) reasons for engaging in genetic testing, (c) interest in different types of genetic testing, including for Alzheimer’s disease, Parkinson’s disease, and macular degeneration, and (d) perceived benefits, risks, and limitations of testing.
RESULTS: Previous uptake of genetic testing was limited (medical use: 5.1%; direct-to-consumer: 10.8%), with direct-to-consumer test uptake higher among respondents with household incomes of $100,000 or more. Over half of adults endorsed interest in genetic testing for estimation of disease risk (58.9%), ancestry knowledge (58%), and informing medical care (53.8%). Interest in genetic testing for specific late-onset conditions was even higher, including Alzheimer’s disease (70%), Parkinson’s disease (65.3%), and macular degeneration (64.3%). Multivariable logistic regression models showed that older adults more likely to be interested in genetic testing for medical or disease risk purposes were those with higher levels of education (college degree or higher) and who endorsed the benefits of genetic testing, whereas respondents who endorsed testing risks and limitations were less likely to express interest.
CONCLUSION: While prior use of genetic testing among the middle-to-older age population was low, interest in testing for Alzheimer’s disease and other late-onset conditions was high. This high interest may translate into increased uptake given expanded access to testing and recent treatment advances for Alzheimer’s disease.
CITATION:
S.J. Feldman ; D. Blasco ; M. Mones ; J. Scott Roberts ; (2024): Interest in and Experience with Genetic Testing for Late-Onset Medical Conditions: Results from the National Poll on Healthy Aging. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.69
ASSOCIATION BETWEEN CEREBROSPINAL FLUID STREM2 LEVELS AND DEPRESSION: THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE STUDY
Y. Wang, M. Ye, Q. Ji, Q. Liu, X. Xu, Y. Zhan
J Prev Alz Dis 2024;4(11):1087-1092
Show summaryHide summaryOBJECTIVE: Previous studies demonstrated a significant protective effect of elevated cerebrospinal fluid (CSF) sTREM2 levels on brain structure and cognitive decline. Nonetheless, the role of sTREM2 in the depression progression remains unclear. This study aimed to investigate the association between CSF sTREM2 levels and longitudinal trajectories of depression.
METHODS: Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Study were used. CSF sTREM2 levels and depression were measured using an ELISA-based assay and the Geriatric Depression Scale (GDS-15), respectively. Linear mixed-effect models were employed to assess the relationships between CSF sTREM2 levels and GDS scores.
RESULTS: A total of 1,017 participants were enrolled at baseline, with a mean follow-up time of 4.65 years. Baseline CSF sTREM2 levels were negatively correlated with GDS scores (β=-0.21, P=0.022) after adjustment for age, gender, race/ethnicity, education, APOE ε4 carrier status, TREM2 rare variant carrier status, marital status, smoking, and clinical cognitive status.
CONCLUSION: Our findings suggested that a higher level of CSF sTREM2 was associated with a lower risk of depression.
CITATION:
Y. Wang ; M. Ye ; Q. Ji ; Q. Liu ; X. Xu ; Y. Zhan ; (2024): Association between Cerebrospinal Fluid sTREM2 Levels and Depression: The Alzheimer’s Disease Neuroimaging Initiative Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.70
BIOMARKERS AND COGNITION STUDY, SINGAPORE (BIOCIS): PROTOCOL, STUDY DESIGN, AND PRELIMINARY FINDINGS
Y.J. Leow, J.D.J. Wang, A. Vipin, G.K. Sandhu, S.A. Soo, D. Kumar, A.A. Mohammed, F.Z.B. Zailan, F.P.H.E. Lee, S. Ghildiyal, S.Y. Liew, C. Dang, P. Tanoto, I.Y.Z. Tan, W.F.W. Chong, N. Kandiah
J Prev Alz Dis 2024;4(11):1093-1105
Show summaryHide summaryBACKGROUND: The focus of medicine is shifting from treatment to preventive care. The expression of biomarkers of dementia and Alzheimer’s disease (AD) appear decades before the onset of observable symptoms, and evidence has emerged supporting pharmacological and non-pharmacological interventions to treat modifiable risk factors of dementia. However, there is limited research on the epidemiology, clinical phenotypes, and underlying pathobiology of cognitive diseases in Asian populations.
OBJECTIVES: The objectives of the Biomarkers and Cognition Study, Singapore(BIOCIS) are to characterize the underlying pathobiology of Cognitive Impairment through a longitudinal study incorporating fluid biomarker profiles, neuroimaging, neuropsychological and clinical outcomes in a multi-ethnic Southeast Asian population.
DESIGN, SETTING, PARTICIPANTS: BIOCIS is a 5-year longitudinal study where participants are assessed annually. 2500 participants aged 30 to 95 will be recruited from the community in Singapore. To investigate how pathology presents with or without minimal clinical symptoms and vice versa, CI and unimpaired individuals will be recruited. Participants will undergo assessments to characterise biomarkers of dementia through neuroimaging, fluid biomarkers, cognitive assessments, behavioural and lifestyle profiles, retinal scans and microbiome indicators.
RESULTS: Since commencement of recruitment in February 2022, 1148 participants have been enrolled, comprising 1012 Chinese, 62 Indian, and 35 Malay individuals. Mean age and education is 61.32 years and 14.34 years respectively with 39.8% males. 47.9 % of the cohort are employed and 32.06% have a family history of dementia. The prevalence of cerebral small vessel disease is 90.2% with a mean modified Fazekas white matter hyperintensity score of 4.1.
CONCLUSION: The BIOCIS cohort will help identify novel biomarkers, pathological trajectories, epidemiology of dementia, and reversible risk factors in a Southeast Asian population. Completion of BIOCIS longitudinal data could provide insights into risk-stratification of Asians populations, and potentially inform public healthcare and precision medicine for better patient outcomes in the prevention of Alzheimer’s disease and dementia.
CITATION:
Y.J. Leow ; J.D.J. Wang ; A. Vipin ; G.K. Sandhu ; S.A. Soo ; D. Kumar ; A.A. Mohammed ; F.Z.B. Zailan ; F.P.H.E. Lee ; S. Ghildiyal ; S.Y. Liew ; C. Dang ; P. Tanoto ; I.Y.Z. Tan ; W.F.W. Chong ; N. Kandiah (2024): Biomarkers and Cognition Study, Singapore (BIOCIS): Protocol, Study Design, and Preliminary Findings. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.89
ALZHEIMER’S DISEASE PREDICTION USING FLY-OPTIMIZED DENSELY CONNECTED CONVOLUTION NEURAL NETWORKS BASED ON MRI IMAGES
R. Sampath, M. Baskar
J Prev Alz Dis 2024;4(11):1106-1121
Show summaryHide summaryAlzheimer’s is a degenerative brain cell disease that affects around 5.8 million people globally. The progressive neurodegenerative disease known as Alzheimer’s Disease (AD), affects the frontal cortex, the part of the brain in charge of memory, language, and cognition. As a result, researchers are utilizing a variety of machine-learning techniques to create an automated method for AD detection. The massive data collected during ROI and biomarker identification takes longer to handle using current methods. This study uses metaheuristic-tuned deep learning to detect the AD-affected region. The research utilizes advanced deep learning and image processing techniques to enhance early and accurate diagnosis of Alzheimer’s disease, potentially enhancing patient outcomes and prompt therapy. The capacity of deep neural networks to extract complex patterns from magnetic resonance imaging (MRI) scans makes them indispensable in the diagnosis of AD since they allow the detection of minor aberrations and complex alterations in brain structure and composition. An adaptive histogram approach processes the collected photographs, and a weighted median filter is used in place of the noisy pixels. The next step is to identify the issue region using a deep convolution network-based clustering segmentation process. A correlated information theory approach is used to extract various textural and statistical features from the separated regions. Lastly, the selected features are probed by the fly-optimized densely linked convolution neural networks. The method surpasses state-of-the-art techniques in sensitivity (15.52%), specificity (15.62%), accuracy (9.01%), error rate (11.29%), and F-measure (10.52%) for recognizing AD-impacted regions in MRI scans using the Kaggle dataset.
CITATION:
R. Sampath ; M. Baskar ; (2024): Alzheimer’s Disease Prediction Using Fly-Optimized Densely Connected Convolution Neural Networks Based on MRI Images. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.66
THE INSULIN SENSITIZER KBP-336 PREVENTS DIABETESINDUCED COGNITIVE DECLINE IN ZDF RATS
A.T. Larsen, K.E. Mohamed, E.A. Petersen, M.A. Karsdal, K. Henriksen
J Prev Alz Dis 2024;4(11):1122-1131
Show summaryHide summaryBACKGROUND AND OBJECTIVES: Diabetes and especially insulin resistance are associated with an increased risk of developing cognitive dysfunction, making anti-diabetic drugs an interesting therapeutic option for the treatment of neurodegenerative disorders. Dual amylin and calcitonin receptor agonists (DACRAs) elicit beneficial effects on glycemic control and insulin sensitivity. However, whether DACRAs affect cognition is unknown.
DESIGN AND INTERVENTION: Zucker Diabetic Fatty rats were treated with either the DACRA KBP-336 (4.5 nmol/kg Q3D), the amylin analog AM1213 (25 nmol/kg QD), or vehicle for 18 weeks. Further, the efficacy of a late KBP-336 intervention was evaluated by including a group starting treatment on day 30. Glucose control and tolerance were evaluated throughout the study and spatial learning and memory were evaluated by Morris Water Maze after 17 weeks of treatment.
RESULTS: When evaluating spatial learning, rats receiving KBP-336 throughout the study performed significantly better than AM1213, vehicle, and late intervention KBP-336. Both KBP-336 and AM1213 treatments improved spatial memory compared to the vehicle. The overall performance in the cognitive tests was reflected in the treatment efficacy on glycemic control, where KBP-336 was superior to AM1213.
CONCLUSION: In summary, the DACRA KBP-336 ameliorates diabetes-induced spatial learning and memory impairment in diabetic rats. Further, KBP-336 improves long-term glycemic control superior to the amylin analog AM1213. Taken together, KBP-336 is, due to its anti-diabetic and insulin-sensitizing properties, a promising candidate for the treatment of cognitive impairments.
CITATION:
A.T. Larsen ; K.E. Mohamed ; E.A. Petersen ; M.A. Karsdal ; K. Henriksen (2024): The Insulin Sensitizer KBP-336 Prevents Diabetes-Induced Cognitive decline in ZDF Rats. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.74
SEX DIFFERENCE IN THE ASSOCIATION BETWEEN PRIOR FRACTURE AND SUBSEQUENT RISK OF INCIDENT DEMENTIA: A LONGITUDINAL COHORT STUDY
D. Gao, W. Rong, C. Li, J. Liang, Y. Wang, Y. Pan, W. Zhang, F. Zheng, W. Xie
J Prev Alz Dis 2024;4(11):1132-1139
Show summaryHide summaryBackground: A history of fracture has been associated with increased risk of dementia; however, it is uncertain whether sex difference exists in the association between prior fracture and subsequent risk of incident dementia.
OBJECTIVES: To investigate whether sex modified the relationship between prior fracture and subsequent risk of dementia.
DESIGN: Prospective cohort study.
SETTING: UK Biobank.
PARTICIPANTS: 496,331 participants (54.6% women) free of dementia at baseline.
MEASUREMENTS: History of fracture was self-reported via touchscreen questionnaires at baseline. The primary outcome was all-cause dementia.
RESULTS: Both any fracture and fragility fracture were significantly associated with an increased risk of subsequent all-cause dementia in men (adjusted hazard ratio (HR): 1.28; 95% confidence interval (CI): 1.14-1.43; adjusted HR: 1.48; 95% CI: 1.18-1.87, respectively), but not in women (adjusted HR: 1.04; 95% CI 0.95-1.15; adjusted HR: 1.01; 95% CI: 0.87-1.18, respectively); and these sex-differences were significant (P interaction = 0.006; P interaction = 0.007, respectively). The sex differences in the impacts of different fracture sites (including upper limb, lower limb, spine, and multiple sites) were consistent on all-cause dementia.
CONCLUSIONS: This study demonstrated that prior fracture was associated with an increased risk of dementia in men but not in women, and the sex difference was significant. Previous fracture may be an important marker for identifying subsequent dementia in middle-aged and older men.
CITATION:
D. Gao ; W. Rong ; C. Li ; J. Liang ; Y. Wang ; Y. Pan ; W. Zhang ; F. Zheng ; W. Xie (2024): Sex Difference in the Association between Prior Fracture and Subsequent Risk of Incident Dementia: A Longitudinal Cohort Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.56
ASSOCIATION BETWEEN RESTING HEART RATE AND MACHINE LEARNING-BASED BRAIN AGE IN MIDDLE- AND OLDER-AGE
J. Wang, H. Huang, W. Yang, A. Dove, X. Ma, W. Xu
J Prev Alz Dis 2024;4(11):1140-1147
Show summaryHide summaryBACKGROUND: Resting heart rate (RHR), has been related to increased risk of dementia, but the relationship between RHR and brain age is unclear.
OBJECTIVE: We aimed to investigate the association of RHR with brain age and brain age gap (BAG, the difference between predicted brain age and chronological age) assessed by multimodal Magnetic Resonance Imaging (MRI) in mid- and old-aged adults.
DESIGN: A longitudinal study from the UK Biobank neuroimaging project where participants underwent brain MRI scans 9+ years after baseline.
SETTING: A population-based study.
PARTICIPANTS: A total of 33,381 individuals (mean age 54.74 ± 7.49 years; 53.44% female).
MEASUREMENTS: Baseline RHR was assessed by blood pressure monitor and categorized as <60, 60–69 (reference), 70–79, or ≥80 beats per minute (bpm). Brain age was predicted using LASSO through 1,079 phenotypes in six MRI modalities (including T1-weighted MRI, T2-FLAIR, T2*, diffusion-MRI, task fMRI, and resting-state fMRI). Data were analyzed using linear regression models.
RESULTS: As a continuous variable, higher RHR was associated with older brain age (β for per 1-SD increase: 0.331, 95% [95% confidence interval, CI]: 0.265, 0.398) and larger BAG (β: 0.263, 95% CI: 0.202, 0.324). As a categorical variable, RHR 70-79 bpm and RHR ≥80 bpm were associated with older brain age (β [95% CI]: 0.361 [0.196, 0.526] / 0.737 [0.517, 0.957]) and larger BAG (0.256 [0.105, 0.407] / 0.638 [0.436, 0.839]), but RHR< 60 bpm with younger brain age (-0.324 [-0.500, -0.147]) and smaller BAG (-0.230 [-0.392, -0.067]), compared to the reference group. These associations between elevated RHR and brain age were similar in both middle-aged (<60) and older (≥60) adults, whereas the association of RHR< 60 bpm with younger brain age and larger BAG was only significant among middle-aged adults. In stratification analysis, the association between RHR ≥80 bpm and older brain age was present in people with and without CVDs, while the relation of RHR 70-79 bpm to brain age present only in people with CVD.
CONCLUSION: Higher RHR (>80 bpm) is associated with older brain age, even among middle-aged adults, but RHR< 60 bpm is associated with younger brain age. Greater RHR could be an indicator for accelerated brain aging.
CITATION:
J. Wang ; H. Huang ; W. Yang ; A. Dove ; X. Ma ; W. Xu (2024): Association between Resting Heart Rate and Machine Learning-Based Brain Age in Middle- and Older-Age. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.76
PERIODONTAL DISEASE AND ALZHEIMER’S: INSIGHTS FROM A SYSTEMATIC LITERATURE NETWORK ANALYSIS
A. Villar, S. Paladini, J. Cossatis
J Prev Alz Dis 2024;4(11):1148-1165
Show summaryHide summaryThis study investigated the relationship between periodontal disease (PD) and Alzheimer’s Disease (AD) through a Systematic Literature Network Analysis (SLNA), combining bibliometric analysis with a Systematic Literature Review (SLR). Analyzing 328 documents from 2000 to 2023, we utilized the Bibliometrix R-package for multiple bibliometric analysis. The SLR primarily centered on the 47 most globally cited papers, highlighting influential research. Our study reveals a positive correlation between Periodontal Disease (PD) and Alzheimer’s Disease (AD), grounded in both biological plausibility and a comprehensive review of the literature, yet the exact causal relationship remains a subject of ongoing scientific investigation. We conducted a detailed analysis of the two main pathways by which PD could contribute to brain inflammation: (a) the Inflammatory Cascade, and (b) Microbial Involvement. The results of our SLNA emphasize the importance of oral health in reducing Alzheimer’s risk, suggesting that managing periodontal health could be an integral part of Alzheimer’s prevention and treatment strategies. The insights from this SLNA pave the way for future research and clinical practices, underscoring the necessity of interdisciplinary methods in both the investigation and treatment of neurodegenerative diseases like Alzheimer’s. Furthermore, our study presents a prospective research roadmap to support ongoing advancement in this field.
CITATION:
A. Villar ; S. Paladini ; J. Cossatis (2024): Periodontal Disease and Alzheimer’s: Insights from a Systematic Literature Network Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.79
THE SHAPE TRAIL TEST IS SENSITIVE IN DIFFERENTIATING OLDER ADULTS WITH MILD COGNITIVE IMPAIRMENT: A CULTURE-NEUTRAL FIVE-MINUTE TEST
Z. Ding, A.S. Chan
J Prev Alz Dis 2024;4(11):1166-1176
Show summaryHide summaryINTRODUCTION: The Shape Trail Test (STT) was developed based upon the Trail Making Test, as a culture-neutral test for measuring processing speed and mental flexibility. This study aims to evaluate the accuracy and validity of this five-minute test for differentiating individuals with normal cognition (NC), subjective memory impairment (SMI), and mild cognitive impairment (MCI).
METHOD: The study included 210 participants aged 50-80 years, with 70 participants in each group matched for age, education, and gender.
RESULTS: No significant difference in STT measures was found between the NC and SMI groups. In contrast, both the NC and SMI groups exhibited significantly better performance (shorter completion time in STT-A and STT-B and fewer STT-B errors) than the MCI group. No significant group differences were found in STT-A errors. Stepwise regression analysis identified three significant predictors for classifying the MCI group from the NC and/or SMI groups, including the STT-B completion time, the STT-A errors, and the interaction between STT-B completion time and STT-B errors. The composite score of these three predictors demonstrated good discriminatory power for classifying the MCI group from the other groups, with area under the curves (AUCs) of 0.76 – 0.79 (p < 0.001), sensitivities of 78.6% - 80%, and specificities of 60% - 61.4%. However, none of the STT measures or their interactions were significant predictors for differentiating the SMI group from the NC group. Besides, the STT measures were significantly correlated with age, education, and executive function measures.
DISCUSSION: The STT could be a culture- and language-free, reliable test for assessing executive function and a sensitive test for predicting MCI.
CITATION:
Z. Ding ; A.S. Chan (2024): The Shape Trail Test Is Sensitive in Differentiating Older Adults with Mild Cognitive Impairment: A Culture-neutral Five-minute Test. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.80
LETTER TO THE EDITOR: HYPNOTICS AND INCIDENT DEMENTIA: A RISK ASSESSMENT
T. Kawada
J Prev Alz Dis 2024;4(11):1177
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CITATION:
T. Kawada (2024): Letter to the Editor: Hypnotics and Incident Dementia: A Risk Assessment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.73
LETTER TO THE EDITOR: UPDATE TO: TWO RANDOMIZED PHASE 3 STUDIES OF ADUCANUMAB IN EARLY ALZHEIMER’S DISEASE
C. Rubel, T. Chen, G. Dent
J Prev Alz Dis 2024;4(11):1178-1179
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CITATION:
C. Rubel ; T. Chen ; G. Dent ; (2024): Letter to the Editor: Update to: Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.147