Ahead of print articles
ASSOCIATION OF COGNITIVE RESERVE INDICATOR WITH COGNITIVE DECLINE AND STRUCTURAL BRAIN DIFFERENCES IN MIDDLE AND OLDER AGE: FINDINGS FROM THE UK BIOBANK
W. Yang, J. Wang, J. Guo, A. Dove, X. Qi, D.A. Bennett, W. Xu
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BACKGROUND: Cognitive reserve (CR) contributes to preserving cognition when facing brain aging and damage. CR has been linked to dementia risk in late life. However, the association between CR and cognitive changes and brain imaging measures, especially in midlife, is unclear.
OBJECTIVE: We aimed to explore the association of CR with cognitive decline and structural brain differences in middle and older age.
DESIGN: This longitudinal study was from the UK Biobank project where participants completed baseline surveys between 2006 to 2010 and were followed (mean follow-up: 9 years).
SETTING: A population-based study.
PARTICIPANTS: A total of 42,301 dementia-free participants aged 40–70 were followed-up to detect cognitive changes. A subsample (n=34,041) underwent brain magnetic resonance imaging scans.
MEASUREMENTS: We used latent class analysis to generate a CR indicator (categorized as high, moderate, and low) based on education, occupation, and multiple cognitively stimulating activities. Cognitive tests for global and domain-specific cognition were administrated at baseline and follow-up. Total brain, white matter, grey matter, hippocampal, and white matter hyperintensity volumes (TBV, WMV, GMV, HV, and WMHV) were assessed at the follow-up examination. Data were analyzed using mixed-effects models and analysis of covariance.
RESULTS: At baseline, 16,032 (37.9%), 10,709 (25.3%), and 15,560 (36.8%) participants had low, moderate, and high levels of CR, respectively. Compared with low CR, high CR was associated with slower declines in global cognition (β [95% confidence interval]: 0.10 [0.08, 0.11]), prospective memory (0.10 [0.06, 0.15]), fluid intelligence (0.07 [0.04, 0.10]), and reaction time (0.04 [0.02, 0.06]). Participants with high CR had lower TBV, WMV, GMV, and WMHV, but higher HV when controlling for global cognition (corrected P <0.01 for all). The significant relationships between CR and cognition and TBV were present among both middle-aged (<60 years) and older (≥60 years) participants. The CR-cognition association remained significant despite reductions in brain structural properties.
CONCLUSIONS: Higher CR is associated with slower cognitive decline, higher HV, and lower microvascular burden, especially in middle age. Individuals with high CR could tolerate smaller brain volumes while maintaining cognition. The benefit of CR for cognition is independent of structural brain differences. Our findings highlight the contribution of enhancing CR to helping compensate for neuroimaging alterations and ultimately prevent cognitive decline.
CITATION:
W. Yang ; J. Wang ; J. Guo ; A. Dove ; X. Qi ; D.A. Bennett ; W. Xu ; (2024): Association of Cognitive Reserve Indicator with Cognitive Decline and Structural Brain Differences in Middle and Older Age: Findings from the UK Biobank. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.54
SERUM TAU-A AND TAU-C LEVELS AND THEIR ASSOCIATION WITH COGNITIVE IMPAIRMENT AND DEMENTIA PROGRESSION IN A MEMORY CLINIC DERIVED COHORT
T.M. Axelsen, P. Høgh, A.R. Bihlet, M.A. Karsdal, K. Henriksen, S.G. Hasselbalch, A.H. Simonsen
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BACKGROUND: Serum-measured fragments of Tau cleaved by ADAM-10 (Tau-A) and Caspase-3 (Tau-C) have been found linked to change in cognitive function and risk of dementia.
OBJECTIVES: 1) To determine the discriminatory abilities of Tau-A, and Tau-C in subjects with either mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) or AD dementia compared to a control group. 2) To determine if there is a relation between Tau-A, and Tau-C and established cerebrospinal fluid (CSF) markers of AD– β-Amyloid1-42 (AB42), Phosphorylated-tau-181 (p-tau), and total-tau. 3) To determine if Tau-A and Tau-C are associated with progression rate from MCI due to AD to AD dementia.
DESIGN: Cross-sectional and a substudy using a retrospective cohort design.
SETTING: Memory clinic derived subjects contributing to the Danish Dementia Biobank.
PARTICIPANTS: Cognitively unimpaired subjects (n=49), patients with mild cognitive impairment (MCI) due to AD (n=45), and Alzheimer’s dementia (n=52).
MEASUREMENTS: Competitive enzyme-linked immunosorbent assay (ELISA)-measured serum levels of Tau-A, and Tau-C.
RESULTS: The ratio between Tau-A and Tau-C differed between the three groups (p=0.015). Age- and sex-adjusted Tau-A differed between groups with lower ratios being associated with more severe disease (p=0.023). Tau-C was trending towards significant correlation to CSF-levels of AB42 (Pearson correlation coefficient 0.164, p=0.051). Those with Tau-C-levels in the 2nd quartile had a hazard ratio (HR) of 2.91 (95% CI 1.01 – 8.44, p=0.04) of progression compared to those in the 1st quartile. Those in the 3rd quartile was found to have a borderline significant (p=0.055) HR of 2.63 (95% CI 0.98 – 7.05) when compared to those in the lowest quartile.
CONCLUSIONS: Tau-A and the ratio between Tau-A and Tau-C showed significant differences between groups and were correlated to CSF-AB42. Tau-C values in the middle range were associated with faster progression from MCI to dementia. This pilot study adds to the mounting data suggesting serum-measured Tau-A and Tau-C as biomarkers useful in relation to diagnosis and progression rate in AD but need further validation.
CITATION:
T.M. Axelsen ; P. Høgh ; A.R. Bihlet ; M.A. Karsdal ; K. Henriksen ; S.G. Hasselbalch ; A.H. Simonsen (2024): Serum Tau-A and Tau-C Levels and Their Association with Cognitive Impairment and Dementia Progression in a Memory Clinic Derived Cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.43
LONGITUDINAL IMPACTS OF PRECISION GREENNESS ON ALZHEIMER’S DISEASE
S.C. Brown, W.W. Aitken, J. Lombard, A. Parrish, J.R. Dewald, R. Ma, S. Messinger, S. Liu, M.I. Nardi, T. Rundek, J. Szapocznik
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BACKGROUND: The potential for greenness as a novel protective factor for Alzheimer’s disease (AD) requires further exploration.
OBJECTIVES: This study assesses prospectively and longitudinally the association between precision greenness - greenness measured at the micro-environmental level, defined as the Census block - and AD incidence.
DESIGN: Older adults living in consistently high greenness Census blocks across 2011 and 2016 were compared to those living in consistently low greenness blocks on AD incidence during 2012-2016.
SETTING: Miami-Dade County, Florida, USA.
PARTICIPANTS: 230,738 U.S. Medicare beneficiaries.
MEASUREMENTS: U.S. Centers for Medicare and Medicaid Services Chronic Condition Algorithm for AD based on ICD-9 codes, Normalized Difference Vegetation Index, age, sex, race/ethnicity, neighborhood income, and walkability.
RESULTS: Older adults living in the consistently high greenness tertile, compared to those in the consistently low greenness tertile, had 16% lower odds of AD incidence (OR=0.84, 95% CI: 0.76-0.94, p=0.0014), adjusting for age, sex, race/ethnicity, and neighborhood income. Age, neighborhood income and walkability moderated greenness’ relationship to odds of AD incidence, such that younger ages (65-74), lower-income, and non-car dependent neighborhoods may benefit most from high greenness.
CONCLUSIONS: High greenness, compared to low greenness, is associated with lower 5-year AD incidence. Residents who are younger and/or who reside in lower-income, walkable neighborhoods may benefit the most from high greenness. These findings suggest that consistently high greenness at the Census block-level, may be associated with reduced odds of AD incidence at a population level.
CITATION:
S.C. Brown ; W.W. Aitken ; J. Lombard ; A. Parrish ; J.R. Dewald ; R. Ma ; S. Messinger ; S. Liu ; M.I. Nardi ; T. Rundek ; J. Szapocznik (2024): Longitudinal Impacts of Precision Greenness on Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.38
COGNITIVE TRAINING WITH OLDER ADULTS USING SMARTPHONE AND WEB-BASED APPLICATIONS: A SCOPING REVIEW
A.F. Silva, R.M. Silva, E. Murawska-Cia?owicz, G. Zurek, N. Danek, M. Cialowicz, J. Carvalho, F.M. Clemente
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INTRODUCTION: The present scoping review focused on: i) which apps were previously studied; ii) what is the most common frequency for implementing cognitive training; and iii) what cognitive functions the interventions most focus on.
METHODS: PRISMA guidelines were followed, and the search was conducted on Web of Science, PsycInfo, Cochrane, and Pubmed. From 1733 studies found, 34 were included.
RESULTS: it was highlighted the necessity for forthcoming investigations to tackle the methodical restrictions and disparities in the domain.
DISCUSSION: great diversity in intervention protocols was found. Incorporating evaluations of physical fitness in conjunction with cognitive evaluations can offer a more all-encompassing comprehension of the impacts of combined interventions. Furthermore, exploring the efficacy of cognitive training applications requires additional scrutiny, considering individual variances and practical outcomes in real-life settings.
CITATION:
A.F. Silva ; R.M. Silva ; E. Murawska-Ciałowicz ; G. Zurek ; N. Danek ; M. Cialowicz ; J. Carvalho ; F.M. Clemente (2024): Cognitive Training with Older Adults Using Smartphone and Web-Based Applications: A Scoping Review. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.17
ANTI-HYPERTENSIVE DRUGS MODERATE THE RELATIONSHIP OF BLOOD PRESSURE WITH ALZHEIMER’S PATHOLOGIES AND NEURODEGENERATIVE MARKERS IN NON-DEMENTED HYPERTENSIVE OLDER ADULTS
Y. Guo, C.-C. Tan, M.-S. Tan, L. Tan, W. Xu, for the Alzheimer’s Disease Neuroimaging Initiative
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BACKGROUND: We aimed to explore whether the relationships of blood pressures (BPs) with Alzheimer’s disease (AD) endophenotypes varied by usage of antihypertensive drugs (AHDs).
METHODS: A total of 765 non-demented older adults (mean age: 74.4 years; female: 43.1%) with a self-reported history of hypertension were followed for 6 years. Multiple linear regression and linear-mixed effect models were used to investigate the interaction effects of five categories of AHDs (angiotensin-converting enzyme inhibitors [ACEI], angiotensin II receptor blockers [ARBs], β-blocker, calcium channel blockers [CCB], diuretic) with BPs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and pulse pressure [PP]) on AD core pathology and neurodegenerative markers.
RESULTS: After Bonferroni correction, significant interaction effects of BPs with AHDs were observed. Elevated SBP or PP in late-life was associated with higher levels of cerebral Aβ burden (diuretic alone/β-blocker × SBP), higher levels of CSF tau proteins (diuretic × SBP/PP, ARBs/CCB × SBP), and lower volume of entorhinal region (β-blocker × SBP, diuretic × PP) only among hypertensive patients who received no anti-hypertensive treatments, while these associations became compromised or null for users of specific AHDs except for ACEI. Compared to taking other classes of AHDs, elevated SBP in late-life was associated with lower cerebral Aβ burden in diuretic users (padjusted = 0.08) and was associated with higher CSF tau proteins in ACEI alone users (padjusted = 0.03). Longitudinal data validated the above-mentioned interaction effects on changes of cerebral Aβ burden (padjusted < 0.05), CSF tau proteins (padjusted < 0.10), and brain atrophy (padjusted < 0.05).
CONCLUSIONS: The relationships of late-life BP with AD pathology and neurodegeneration could be modified by anti-hypertensive treatments and varied by AHD classification. These findings provide preliminary evidence for tailored BP management strategy for preventing AD among late-life hypertensive adults.
CITATION:
Y. Guo ; C.-C. Tan ; M.-S. Tan ; L. Tan ; W. Xu ; for the Alzheimer’s Disease Neuroimaging Initiative (2024): Anti-Hypertensive Drugs Moderate the Relationship of Blood Pressure with Alzheimer’s Pathologies and Neurodegenerative Markers in Non-Demented Hypertensive Older Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.40
USABILITY OF A WEB-BASED REGISTRY FOR PRECLINICAL ALZHEIMER’S DISEASE: IMPLICATIONS FROM A CROSSSECTIONAL ONLINE SURVEY
K. Sato, Y. Niimi, R. Ihara, K. Suzuki, A. Iwata, T. Iwatsubo
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BACKGROUND: We have been conducting a Japanese trial-ready cohort web study since 2019 as a web-based online registry to enroll individuals with preclinical Alzheimer’s disease to facilitate trials on Alzheimer’s disease prevention. The usability of a website might be an important factor in determining user participation and retention.
OBJECTIVES: We conducted a user questionnaire survey to analyze the usability of the Japanese trial-ready cohort website and user characteristics for future website improvement.
DESIGN: This was a cross-sectional prospective observational study.
SETTING: Online survey using Google Forms.
PARTICIPANTS: Among the Japanese trial-ready cohort web study participants, we enrolled those who provided consent to participate in the study and had completed one or more Cognitive Function Instrument tests before May 2, 2023. We sent an invitation e-mail, including the questionnaire web address, to eligible participants on July 21 and 22, 2023.
MEASUREMENTS: We analyzed the questionnaire answers, including the system usability scale score and time of response (in 24 h). We also compared the respondents’ characteristics with that of all the Japanese trial-ready cohort web study participants to identify features associated with an increased/decreased response rate to the questionnaire.
RESULTS: Among the 10,112 Japanese trial-ready cohort web study participants that we sent invitation e-mails, we received 1,574 eligible responses (15.6%) within three weeks of the response acceptance period. The mean system usability scale score was 67.6, and no difference in system usability scale scores was observed in terms of age or sex. Approximately half of the respondents of the Japanese trial-ready cohort web study heard about it online, whereas one-fourth heard about it via newspapers. Contribution to drug development for dementia treatment was the most frequent motivation for participating in the Japanese trial-ready cohort web study (51.5%), followed by participation in the latest research (48.1%), concerns about self-memory (43.4%), and a family history of dementia (34.6%). Female respondents responded approximately 1.5 h later than male respondents. Lastly, those who had participated in the Japanese trial-ready cohort onsite study, were in their 70’s, or had a larger number of Cognitive Function Instrument or Cogstate tests completion history were more likely to respond to the current online survey (relative risk of response > 1).
CONCLUSIONS: We conducted an online survey using Google Forms for participants in the Japanese trial-ready cohort web study to determine the usability. The results of this study might help to improve the user experience of the Japanese trial-ready cohort website itself, increase the web study registrants, maintain user retention, facilitate future online surveys, and serve as a reference for other web-based registries of presymptomatic disease status.
CITATION:
K. Sato ; Y. Niimi ; R. Ihara ; K. Suzuki ; A. Iwata ; T. Iwatsubo ; (2024): Usability of a Web-Based Registry for Preclinical Alzheimer’s Disease: Implications from a Cross-Sectional Online Survey. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.48
ASSOCIATIONS AND POTENTIAL MULTIPLE MECHANISMS BETWEEN SUBJECTIVE HEARING LOSS AND COGNITIVE IMPAIRMENT
L. Cui, Y.-Y. Tu, Z. Zhang, Y.-H. Guo, Y.-H. Guan, F. Xie, Q.-H. Guo
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BACKGROUND: Subjective hearing loss (SHL) refers to an individual’s self-assessment of their hearing loss. The association and underlying mechanisms between SHL and cognitive impairment still necessitate elucidation.
OBJECTIVES: To validate potential mechanisms between SHL and cognitive impairment.
DESIGN: Cross-section.
SETTING: Shanghai, China.
PARTICIPANTS: A total of 2369 individuals from communities and the cognitive disorder clinic.
MEASUREMENTS: All participants were subjected to a comprehensive neuropsychological assessment, encompassing the Hearing Handicap Inventory for the Elderly-Screening Version (HHIE-S). The participants’ brain β-amyloid (Aβ) deposition status, plasma biomarkers associated with Alzheimer’s disease (AD), and cardiovascular risk factors were also collected.
RESULTS: In individuals with a heightened SHL, elevated HHIE-S score was linked to diminished cognitive and daily functioning as well as heightened levels of depressed mood. This correlation was observed in auditory memory performance but not in visual memory. The influence of SHL on cognitive function was mediated by depressed mood. SHL was associated with diabetes and smoking, whereas cognitive function was associated with hyperlipidemia and alcohol consumption. In individuals with positive brain Aβ deposition, SHL demonstrated associations with cognitive function independent of plasma Aβ42/40 ratio, P-tau181, neurofilament light chain, and APOE allele status.
CONCLUSION: SHL has an independent effect on cognitive impairment. The findings do no provide evidence for the common cause mechanism. Instead, the findings support the presence of a cognitive resource mechanism and an impoverished environment mechanism, along with the potential for a pathological interaction mechanism.
CITATION:
L. Cui ; Y.-Y. Tu ; Z. Zhang ; Y.-H. Guo ; Y.-H. Guan ; F. Xie ; Q.-H. Guo (2024): Associations and Potential Multiple Mechanisms between Subjective Hearing Loss and Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.62
WHO BENEFITED MOST FROM THE INTERNET-BASED CONVERSATIONAL ENGAGEMENT RCT (I-CONECT)? APPLICATION OF THE PERSONALIZED MEDICINE APPROACH TO A BEHAVIORAL INTERVENTION STUDY
C.-Y. Wu, K. Yu, S.E. Arnold, S. Das, H.H. Dodge
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BACKGROUND: Many Alzheimer’s Disease (AD) clinical trials have failed to demonstrate treatment efficacy on cognition. It is conceivable that a complex disease like AD may not have the same treatment effect due to many heterogeneities of disease processes and individual traits.
OBJECTIVES: We employed an individual-level treatment response (ITR) approach to determine the characteristics of treatment responders and estimated time saved in cognitive decline using the Internet-based Conversational Engagement Clinical Trial (I-CONECT) behavioral intervention study as a model.
DESIGN AND SETTING: I-CONECT is a multi-site, single-blind, randomized controlled trial aimed to improve cognitive functions through frequent conversational interactions via internet/webcam. The experimental group engaged in video chats with study staff 4 times/week for 6 months; the control group received weekly 10-minute check-in phone calls.
PARTICIPANTS: Out of 186 randomized participants, current study used 139 participants with complete information on both baseline and 6-month follow-up (73 with mild cognitive impairment (MCI), 66 with normal cognition; 64 in the experimental group, and 75 in the control group).
MEASUREMENTS: ITR scores were generated for the Montreal Cognitive Assessment (MoCA) (global cognition, primary outcome) and Category Fluency Animals (CFA) (semantic fluency, secondary outcome) that showed significant efficacy in the trial. ITR scores were generated through 300 iterations of 3-fold cross-validated random forest models. The average treatment difference (ATD) curve and the area between the curves (ABC) were estimated to measure the heterogeneity of treatment responses. Responder traits were identified using SHapley Additive exPlanations (SHAP) and decision tree models. The time saved in cognitive decline was explored to gauge clinical meaningfulness.
RESULTS: ABC statistics showed substantial heterogeneity in treatment response with MoCA but modest heterogeneity in treatment response with CFA. Age, cognitive status, time spent with family and friends, education, and personality were important characteristics that influenced treatment responses. Intervention group participants in the upper 30% of ITR scores demonstrated potential delays of 3 months in semantic fluency (CFA) and 6 months in global cognition (MoCA), assuming a 5-fold faster natural cognitive decline compared to the control group during the post-treatment period.
CONCLUSIONS: ITR-based analyses are valuable in profiling treatment responders for features that can inform future trial design and clinical practice. Reliably measuring time saved in cognitive decline is an area of ongoing research to gain insight into the clinical meaningfulness of treatment.
CITATION:
C.-Y. Wu ; K. Yu ; S.E. Arnold ; S. Das ; H.H. Dodge (2024): Who Benefited Most from the Internet-Based Conversational Engagement RCT (I-CONECT)? Application of the Personalized Medicine Approach to a Behavioral Intervention Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.41
FISH AND SHELLFISH CONSUMPTION, COGNITIVE HEALTH AND MORTALITY FROM ALZHEIMER’S DISEASE AMONG US ADULTS AGED 60 AND OLDER
H. Sun
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BACKGROUND: Relationships of fish-shellfish consumption, cognitive health and mortality from Alzheimer’s disease (AD) among US adults aged 60 years and older have not been adequately studied.
OBJECTIVES: To determine the relationship of fish-shellfish consumption, cognitive health and mortality from AD in US adults aged 60 years and older.
DESIGN, SETTING AND PARTICIPANTS: The data of this cross-sectional study of US adults aged 60 years and older were from the National Nutrition and Health Examination Survey (NHANES) datasets. Frequency of fish-shellfish consumption, its association with subjective cognitive decline (SCD) and AD mortality of these participants between 1999 and 2018 and cognitive assessment scores between 2011 and 2014 were analyzed.
MEASUREMENTS AND RESULTS: US adults aged 60 years and older consumed fish-shellfish 1.2 times/week and had a blood Hg of 1.63 ug/L on average between 1999 and 2018. Participants aged 60 years and older in the highest quartile of fish-shellfish consumption (~3 times/week) had significantly higher cognitive assessment scores than those in the lowest quartile (rare or no fish-shellfish consumption). Adults in the highest quartile of fish-shellfish consumption had a 30% lower risk (odds ratio 0.7, 95%CI 0.57-0.87) of SCD, and 44% lower risk (hazard ratio 0.56, 95%CI 0.35-0.9) of AD mortality than those in the lowest quartile.
CONCLUSION: Increased fish-shellfish consumption was associated with improved scores of cognitive assessment and reduced risks of SCD and AD mortality.
CITATION:
H. Sun (2024): Fish and Shellfish Consumption, Cognitive Health and Mortality from Alzheimer’s Disease among US Adults Aged 60 and Older. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.57
THE EFFECTS OF DIFFERENT EXERCISE INTERVENTIONS ON PATIENTS WITH SUBJECTIVE COGNITIVE DECLINE: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS
R. Chen, B. Zhao, J. Huang, M. Zhang, Y. Wang, J. Fu, H. Liang, H. Zhan
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BACKGROUND AND OBJECTIVE: Exercise is a promising non-pharmacological therapy for subjective cognitive decline, but it is unclear which type of exercise is most effective. The objective was to assess the comparative effects and ranks of all exercise-based interventions on cognitive function in patients with subjective cognitive decline (SCD).
METHOD: In this network meta-analysis, Online databases for Web of Science, PubMed, Embase, Medline, Cochrane Library and PsycINFO were searched from inception to April 30, 2023. The included studies are randomized controlled trials assessing the efficacy of exercise interventions for individuals with SCD. The primary outcome measure is memory, while secondary outcome measures encompass executive function, attention, verbal fluency, and global cognitive function. Represented using Standardized Mean Differences (SMDs) along with their 95% Confidence Intervals (CIs). Bias assessment was conducted in accordance with the ‘Cochrane Risk of Bias Assessment Tool, 2nd Edition’ (RoB 2). Pairwise meta-analysis was carried out using the ‘meta-analysis’ module within STATA 14.0, and network meta-analysis was performed using the ‘mvmeta’ and ‘network’ packages available in STATA 14.0. Registration number CRD42023289687.
RESULT: This study included a total of 11 randomized controlled trials, encompassing 1,166 patients. Mind-body exercise was found to be efficacious in enhancing or sustaining memory (SMD: 0.58, 95%CI: 0.06 ~ 1.10) and executive function (SMD: 0.41, 95%CI: 0.09 ~ 0.73) in individuals with subjective cognitive decline. Furthermore, mind-body exercise exhibited the highest probability of being the most effective measures for improving or preventing the decline in memory (surface under cumulative ranking curve (SUCRA) value: 90.4) and executive function (SUCRA value: 91.8). The second-ranked moderate-intensity aerobic exercise has also shown a positive effect on the improvement of executive function in patients with subjective cognitive decline (SMD: 0.23, 95%CI: 0.03 ~ 0.43, SUCRA value: 68.2). However, we did not observe a significant effectiveness of exercise interventions on verbal fluency, attention, and overall cognitive function in subjective cognitive decline.
CONCLUSION: Mind-body exercise may potentially be the optimal strategies for enhancing memory and executive function in individuals with subjective cognitive decline. Additionally, moderate-intensity aerobic exercise has shown a modest positive effect on executive function in subjective cognitive decline. When resources permit, practical application of these findings may be considered. Nevertheless, further support for the conclusions of this study is warranted through larger sample sizes and well-designed multicenter trials.
CITATION:
R. Chen ; B. Zhao ; J. Huang ; M. Zhang ; Y. Wang ; J. Fu ; H. Liang ; H. Zhan (2024): The Effects of Different Exercise Interventions on Patients with Subjective Cognitive Decline: A Systematic Review and Network Meta-Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.65
SUSTAINABLE PARTICIPATION IN COMMUNITY HEALTH PROGRAMS TO PROMOTE A HEALTHY LIFESTYLE AND PREVENT AND PROTECT AGAINST DEMENTIA AMONG RURAL TAIWANESE MIDDLE-AGED AND OLDER ADULTS
L. Chang, S.-C. Chen, P.-Y. Lin, M.-C. Chen, L.-L. Liao, H.-P. Lin, Y.-Y. Tsao, M.-C. Chen
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BACKGROUND: Resource and economic constraints limit access to health care in rural populations, and consequently, rates of chronic illnesses are higher in this population. Further, little is known about how rural populations adopt active and healthy lifestyle behavior for dementia prevention.
OBJECTIVES: This study aimed to explore the impact of modification in lifestyle behaviors on changes in cognitive function among middle-aged and older adults living in a rural area of Taiwan.
DESIGN: In this prospective longitudinal study, changes in lifestyle and cognitive function were compared between the experimental and control groups.
SETTING: Six rural community care stations were randomly cluster sampled in southern Taiwan.
PARTICIPANTS: A total of 155 participants were enrolled and classified into two groups according to their community activity participation rate (CAPR). The control group (n=68) had a CAPR < 1x/month, and the experimental group (n=87) had a CAPR > 1x/month.
MEASUREMENTS: Cognitive function of the participants was measured using the MMSE scale. Lifestyle behaviors were measured using a self-designed questionnaire based on the Transtheoretical Model.
RESULTS: From 2018-2020, the experimental group successfully maintained a healthy lifestyle. The MMSE score in the experimental group was significantly higher in the 3rd year than that in the control group (25.37 vs 22.56, p < 0.001).
CONCLUSIONS: Sustainable community participation and adopting a healthy lifestyle could effectively maintain the cognitive function of the study participants. However, more needs to be done to support rural older adults to maintain a healthy diet and control their weight.
CITATION:
L. Chang ; S.-C. Chen ; P.-Y. Lin ; M.-C. Chen ; L.-L. Liao ; H.-P. Lin ; Y.-Y. Tsao ; M.-C. Chen (2024): Sustainable Participation in Community Health Programs to Promote a Healthy Lifestyle and Prevent and Protect against Dementia among Rural Taiwanese Middle-Aged and Older Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.45
THE MULTI-DOMAIN LIFESTYLE INTERVENTION FOR COGNITIVE IMPAIRMENT IN COMMUNITY-DWELLING OLDER ADULTS IN HANGZHOU (THE HERITAGE STUDY): STUDY DESIGN AND PROTOCOL
X. Xu, T. Pang, Y. Zhou, H. Zhang, A. Ma, C. Yuan, H. Chen, X. Wen, Q. Yang, X. Xu
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BACKGROUND: The globe has been working to promote a multi-domain lifestyle intervention for dementia prevention in older adults, referring to the Worldwide-FINGERS (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) initiative. In China, the multi-domain lifestyle intervention has been implemented in rural communities (MIND-China), yet the adaptability of such intervention based on the urban communities in China has not been verified.
OBJECTIVE: To examine the effectiveness and feasibility of the multi-domain lifestyle intervention on dementia prevention in at-risk community-dwelling older adults in China.
DESIGN, SETTING, PARTICIPANTS: The multi-domain lifestyle intervention study is a community-based 2-year cluster randomized controlled trial (RCT). A total of 1200 participants aged 60-80 years old will be recruited from twelve communities in Hangzhou, Zhejiang. Inclusion criteria were the Montreal Cognitive Assessment 5 minutes protocol (5 min MoCA) score of 6-9 or the Ascertain Dementia 8 (AD 8) score of ≥2, and having modifiable lifestyle factors.
INTERVENTION, MEASUREMENTS, RESULTS: Participating communities will be randomized into either the structured multi-domain intervention (SMI) arm or the self-guided intervention (SGI, general health education) arm. The SMI consists of cognitive training, physical exercise, and nutritional and dietary instruction for the first 12 months; and vascular risks monitoring and control for 24 months. The primary outcome is the global cognitive performance, measured by the comprehensive Neuropsychological Test Battery (NTB). The secondary outcomes include domain-specific cognitive performances, physical function, mental health, physiological and biochemical indices, adherence to healthy lifestyles, and neuroimaging metrics. The feasibility of intervention will be evaluated around the five dimensions of the RE-AIM framework and in conjunction with quantitative data, operational data and results of focus group discussions.
CONCLUSIONS: Following the Worldwide-FINGERS, this cluster RCT will verify the adaptability of the multi-domain lifestyle intervention in the urban community settings in China. This study will add evidence for global dementia prevention and management among older adults.
CITATION:
X. Xu ; T. Pang ; Y. Zhou ; H. Zhang ; A. Ma ; C. Yuan ; H. Chen ; X. Wen ; Q. Yang ; X. Xu (2024): The Multi-domain Lifestyle Intervention for Cognitive Impairment in Community-Dwelling Older Adults in Hangzhou (The Heritage Study): Study Design and Protocol. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.59
CHINA INITIATIVE FOR MULTI-DOMAIN INTERVENTION (CHINA-IN-MUDI) TO PREVENT COGNITIVE DECLINE: STUDY DESIGN AND PROGRESS
S.-Y. Li, X.-Y. Xie, D. Liu, G.-R. Cheng, F.-F. Hu, D.-Y. Zeng, X.-C. Chen, L.-F. Jia, Y.-J. Wang, X.-L. Bu, C. Qiu, F. Gao, J.-G. Gu, M.-F. Liu, Y. Li, Y.-L. Zhou, H.-J. Chang, Y.-M. Ou, L. Xu, Z.-X. Wu, J.-J. Zhang, J.-Y. Wang, L.-Y. Huang, Y.-Y. Cui, J. Zhou, X.-C. Liu, J. Liu, Q.-Q. Nie, D. Song, C. Cai, G.-B. Han, X. Yang, W. Tan, J.-T. Yu, Y. Zeng
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BACKGROUND: Alzheimer’s disease (AD), the most common type of irreversible dementia, is predicted to affect 152 million people by 2050. Evidence from large-scale preventive randomized controlled trials (RCTs) on modifiable risk variables in Europe has shown that multi-domain lifestyle treatments for older persons at high risk of dementia may be practical and effective. Given the substantial differences between the Chinese and European populations in terms of demographics and living conditions, direct adoption of the European program in China remains unfeasible. Although a RCT has been conducted in China previously, its participants were mainly from rural areas in northern China and, thus, are not representative of the entire nation.There is an urgent need to establish cohorts that represent different economic, cultural, and geographical situations in order to explore implementation strategies and evaluate the effects of early multi-domain interventions more comprehensively and accurately.
MEDTODS: We developed an integrated intervention procedure implemented in urban neighborhood settings, namely China Initiative for Multi-Domain Intervention (CHINA-IN-MUDI). CHINA-IN-MUDI is a 2-year multicenter open-label cluster-randomised controlled trial centered around a Chinese-style multi-domain intervention to prevent cognitive decline. Participants aged 60–80 years were recruited from a nationally representative study, i.e. China Healthy Aging and Dementia Study cohort. An external harmonization process was carried out to preserve the original FINGER design. Subsequently, we standardized a series of Chinese-style intervention programs to align with cultural and socioeconomic status. Additionally, we expanded the secondary outcome list to include genomic and proteomic analyses. To enhance adherence and facilitate implementation, we leveraged an e-health application.
RESULTS: Screening commenced in July 2022. Currently, 1,965 participants have been randomized into lifestyle intervention (n = 772) and control groups (n = 1,193). Both the intervention and control groups exhibited similar baseline characteristics. Several lifestyle and vascular risk factors were present, indicating a potential window of opportunity for intervention. The intervention will be completed by 2025.
CONCLUSIONS: This project will contribute to the evaluation of the effectiveness and safety of intervention strategies in controlling AD risk and reducing clinical events, providing a basis for public health decision-making in China.
CITATION:
S.-Y. Li ; X.-Y. Xie ; D. Liu ; G.-R. Cheng ; F.-F. Hu ; D.-Y. Zeng ; X.-C. Chen ; L.-F. Jia ; Y.-J. Wang ; X.-L. Bu ; C. Qiu ; F. Gao ; J.-G. Gu ; M.-F. Liu ; Y. Li ; Y.-L. Zhou ; H.-J. Chang ; Y.-M. Ou ; L. Xu ; Z.-X. Wu ; J.-J. Zhang ; J.-Y. Wang ; L.-Y. Huang ; Y.-Y. Cui ; J. Zhou ; X.-C. Liu ; J. Liu ; Q.-Q. Nie ; D. Song ; C. Cai ; G.-B. Han ; X. Yang ; W. Tan ; J.-T. Yu ; Y. Zeng ; (2024): China Initiative for Multi-Domain Intervention (CHINA-IN-MUDI) to Prevent Cognitive Decline: Study Design and Progress. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.63
CRITICAL VALUES OF DAILY SEDENTARY TIME AND ITS LONGITUDINAL ASSOCIATION WITH MILD COGNITIVE IMPAIRMENT CONSIDERING APOE Ε4: A PROSPECTIVE COHORT STUDY
H. Duan, X. He, T. Yang, N. Xu, Z. Wan, Z. Li, Y. Chen, Y. Du, M. Zhang, J. Yan, C. Sun, G. Wang, F. Ma, W. Li, X. Li, G. Huang
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BACKGROUND: Long sedentary time and physical inactivity are negatively related to cognition, but the cut-off value remains unclear, and apolipoprotein E polymorphism ε4 (APOE ε4) is a known genetic risk factor of mild cognitive impairment (MCI).
OBJECTIVES: To explore longitudinal association of sedentary time and MCI, and to identify a cutoff value that increases the risk of developing MCI, taking into account APOE ε4 stratification and its interactions.
DESIGN: A prospective cohort study.
SETTING: Population-based study.
PARTICIPANTS: We included 4932 older adults from Tianjin Elderly Nutrition and Cognition (TENC) cohort study recruited from March 2018 to June 2021 with 3.11 years of median follow-up time.
MEASUREMENTS: The primary outcome was newly diagnosed MCI, which was diagnosed by a modified version of the Petersen’s criteria. The information of sedentary time (hours/day) and physical activity (MET-h/week) were obtained by questionnaire. Cox proportional hazard regression models and restricted spline curve were conducted.
RESULTS: A total of 4932 participants were included (mean [SD] age, 67.85 [4.96] years; 2627 female [53.3%] and 2305 male [46.7%]), 740 newly onset MCI patients were identified. Longer sedentary time was associated with higher risk of MCI for all participants (HR:1.069, 95%CI: 1.034, 1.105), especially in APOE ε4 non-carriers (HR:1.083, 95%CI: 1.045, 1.123) whether adjusted potential confounders. Sedentary time had synergistic interactions with APOE ε4 (β:1.503, 95%CI: 1.163, 1.942) and physical activities (β: 1.495, 95%CI: 1.210, 1.846). Restricted spline curve showed a cut-off value of 3.03 hours/day.
CONCLUSIONS: Long sedentary time (≥3.03 hours/day) could increase MCI risk, especially in APOE ε4 non-carriers, people with higher PA, aged 65 and above.
CITATION:
H. Duan ; X. He ; T. Yang ; N. Xu ; Z. Wang ; Z. Li ; Y. Chen ; Y. Du ; M. Zhang ; J. Yan ; C. Sun ; G. Wang ; F. Ma ; W. Li ; X. Li ; G. Huang (2024): Critical Values of Daily Sedentary Time and Its Longitudinal Association with Mild Cognitive Impairment Considering APOE ε4: A Prospective Cohort Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.44
DOMINANTLY INHERITED ALZHEIMER NETWORK TRIALS UNIT (DIAN-TU): TRIAL SATISFACTION AND ATTITUDES TOWARDS FUTURE CLINICAL TRIALS
H. Liu, J. Li, E. Ziegemeier, S. Adams, E. McDade, D.B. Clifford, Y. Cao, G. Wang, Y. Li, S.L. Mills, A.M. Santacruz, S. Belyew, J.D. Grill, B.J. Snider, C.J. Mummery, G. Surti, D. Hannequin, D. Wallon, S.B. Berman, I.Z. Jimenez-Velazquez, E.D. Roberson, C.H. van Dyck, L.S. Honig, R. Sanchez-Valle, W.S. Brooks, S. Gauthier, D. Galasko, C.L. Masters, J. Brosch, G.-Y.R. Hsiung, S. Jayadev, M. Formaglio, M. Masellis, R. Clarnette, J. Pariente, B. Dubois, F. Pasquier, R.J. Bateman, J.J. Llibre-Guerra, for the DIAN-TU Study Team
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BACKGROUND: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU).
METHODS: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants’ clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials.
RESULTS: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial’s demographic distribution. Participants’ decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome.
CONCLUSION: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.
CITATION:
H. Liu ; J. Li ; E. Ziegemeier ; S. Adams ; E. McDade ; D.B. Clifford ; Y. Cao ; G. Wang ; Y. Li ; S.L. Mills ; A.M. Santacruz ; S. Belyew ; J.D. Grill ; B.J. Snider ; C.J. Mummery ; G. Surti ; D. Hannequin ; D. Wallon ; S.B. Berman ; I.Z. Jimenez-Velazquez ; E.D. Roberson ; C.H. van Dyck ; L.S. Honig ; R. Sanchez-Valle ; W.S. Brooks ; S. Gauthier ; D. Galasko ; C.L. Masters ; J. Brosch ; G.-Y.R. Hsiung ; S. Jayadev ; M. Formaglio ; M. Masellis ; R. Clarnette ; J. Pariente ; B. Dubois ; F. Pasquier ; R.J. Bateman ; J.J. Llibre-Guerra ; for the DIAN-TU Study Team (2024): Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU): Trial Satisfaction and Attitudes towards Future Clinical Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.61
24-HOUR BLOOD PRESSURE VARIABILITY VIA AMBULATORY MONITORING AND RISK FOR PROBABLE DEMENTIA IN THE SPRINT TRIAL
I.J. Sible, D.A. Nation
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Background: Blood pressure variability is an emerging risk factor for dementia, independent and oftentimes beyond mean blood pressure levels. Recent evidence from interventional cohorts with rigorously controlled mean blood pressure levels suggest blood pressure variability over months to years remains a risk for dementia, but no prior studies have investigated relationships with blood pressure variability over shorter time periods.
OBJECTIVES: To investigate the potential effect of ambulatory blood pressure variability on the rate of cognitive outcomes under intensive vs standard blood pressure lowering.
DESIGN: Post hoc analysis of the randomized, controlled, open-label Systolic Blood Pressure Intervention Trial clinical trial.
SETTING: Multisite Systolic Blood Pressure Intervention Trial.
PARTICIPANTS: 793 participants at increased risk for cardiovascular disease and without history of dementia at study randomization.
INTERVENTION: Standard (<140 mmHg systolic blood pressure target) vs intensive (<120 mmHg systolic blood pressure target) lowering of mean blood pressure.
MEASUREMENTS: 24-hour ambulatory blood pressure monitoring 27 months after treatment randomization (standard vs intensive) and follow-up cognitive testing. Intraindividual blood pressure variability was calculated as the average real variability over 24-hour, daytime, and nighttime periods. Participants were categorized into 3 adjudicated clinical outcomes: no cognitive impairment, mild cognitive impairment, probable dementia. Cox proportional hazards models examined the potential effect of ambulatory blood pressure variability on the rate of cognitive outcomes under intensive vs standard blood pressure lowering. Associations with mean blood pressure were also explored.
RESULTS: Higher systolic 24-hour blood pressure variability was associated with increased risk for probable dementia in the standard group (adjusted hazard ratio [HR]: 2.56 [95% CI 1.16, 5.62], p = 0.019) but not in the intensive group (HR: 0.54 [95% CI 0.24, 1.23], p = 0.141). Similar findings were observed with daytime systolic blood pressure variability but not nighttime blood pressure variability. Mean blood pressure was not associated with cognitive outcomes.
CONCLUSIONS: Higher systolic 24-hour and daytime blood pressure variability via ambulatory monitoring is associated with risk for dementia under standard blood pressure treatment. Findings support prior evidence that blood pressure variability remains a risk for dementia despite strict control of mean blood pressure levels.
CITATION:
I.J. Sible ; D.A. Nation (2024): 24-Hour Blood Pressure Variability Via Ambulatory Monitoring and Risk for Probable Dementia in the SPRINT Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.35
AT-HOME ADMINISTRATION OF GANTENERUMAB BY CARE PARTNERS TO PEOPLE WITH EARLY ALZHEIMER’S DISEASE: FEASIBILITY, SAFETY AND PHARMACODYNAMIC IMPACT
F.G. Boess, M.A. Scelsi, T. Grimmer, R.J. Perry, M. Tonietto, G. Klein, C. Hofmann, M. Salami, J. Wojtowicz, C.J. Lansdall, C. Lane, G.A. Kerchner, J. Smith, R.S. Doody, for the GRADUATION Investigators and the gantenerumab study group
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BACKGROUND: Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer’s disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale – Sum of Boxes), development of gantenerumab in sporadic Alzheimer’s disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies.
OBJECTIVES: To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners.
DESIGN: Phase 2, open-label, single arm study.
SETTING: Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023.
PARTICIPANTS: Participants aged 50 to 90 with early symptomatic Alzheimer’s disease (mild cognitive impairment/mild dementia due to Alzheimer’s disease), and evidence of amyloid positron emission tomography positivity.
INTERVENTION: Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners.
MEASUREMENTS: The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety.
RESULTS: The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6–15.8; n=149) and -35.48 centiloids (range: -63.2–-7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners.
CONCLUSIONS: Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer’s disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer’s disease. Although gantenerumab’s development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-β antibodies and can increase flexibility of drug administration for people living with Alzheimer’s disease and their families.
CITATION:
F.G. Boess ; M.A. Scelsi ; T. Grimmer ; R.J. Perry ; M. Tonietto ; G. Klein ; C. Hofmann ; M. Salami ; J. Wojtowicz ; C.J. Lansdall ; C. Lane ; G.A. Kerchner ; J. Smith ; R.S. Doody ; for the GRADUATION Investigators and the gantenerumab study group ; (2024): At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer’s Disease: Feasibility, Safety and Pharmacodynamic Impact. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.60
PHASE 2A LEARNINGS INCORPORATED INTO REWIND-LB, A PHASE 2B CLINICAL TRIAL OF NEFLAMAPIMOD IN DEMENTIA WITH LEWY BODIES
N.D. Prins, W. de Haan, A. Gardner, K. Blackburn, H.-M. Chu, J.E. Galvin, J.J. Alam
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BACKGROUND: In an exploratory 91-participant phase 2a clinical trial (AscenD-LB, NCT04001517) in dementia with Lewy bodies (DLB), neflamapimod showed improvement over placebo on multiple clinical endpoints. To confirm those results, a phase 2b clinical study (RewinD-LB, NCT05869669 ) that is similar to AscenD-LB has been initiated.
OBJECTIVES: To optimize the choice of patient population, primary endpoint, and biomarker evaluations in RewinD-LB.
DESIGN: Evaluation of the efficacy results from AscenD-LB, the main results of which, and a re-analysis after stratification for absence or presence of AD co-pathology (assessed by plasma ptau181), have been published. In addition, the MRI data from a prior phase 2a clinical trial in Early Alzheimer’s disease (AD), were reviewed.
SETTING: 22 clinical sites in the US and 2 in the Netherlands.
PARTICIPANTS: Probable DLB by consensus criteria and abnormal dopamine uptake by DaTscan™ (Ioflupane I123 SPECT).
INTERVENTION: Neflamapimod 40mg capsules or matching placebo capsules, twice-a-day (BID) or three-times-a-day (TID), for 16 weeks.
MEASUREMENTS: 6-test Neuropsychological Test Battery (NTB) assessing attention and executive function, Clinical Dementia Rating Sum-of-Boxes (CDR-SB), Timed Up and Go (TUG), International Shopping List Test (ISLT).
RESULTS: Within AscenD-LB, patients without evidence of AD co-pathology exhibited a neflamapimod treatment effect that was greater than that in the overall population and substantial (cohen’s d effect size vs. placebo ≥ for CDR-SB, TUG, Attention and ISLT-recognition). In addition, the CDR-SB and TUG performed better than the cognitive tests to demonstrate neflamapimod treatment effect in comparison to placebo. Further, clinical trial simulations indicate with 160-patients (randomized 1:1), RewinD-LB conducted in patients without AD co-pathology has >95% (approaching 100%) statistical power to detect significant improvement over placebo on the CDR-SB. Preliminary evidence of positive treatment effects on beta functional connectivity by EEG and basal forebrain atrophy by MRI were obtained in AscenD-LB and the Early AD study, respectively.
CONCLUSION: In addition to use of a single dose regimen of neflamapimod (40mg TID), key distinctions between phase 2b and phase 2a include RewinD-LB (1) excluding patients with AD co-pathology, (2) having CDR-SB as the primary endpoint, and (3) having MRI studies to evaluate effects on basal forebrain atrophy.
CITATION:
N.D. Prins ; W. de Haan ; A. Gardner ; K. Blackburn ; H.-M. Chu ; J.E. Galvin ; J.J. Alam (2024): Phase 2A Learnings Incorporated into RewinD-LB, a Phase 2B Clinical Trial of Neflamapimod in Dementia with Lewy Bodies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.36
“TIME SAVED” CALCULATIONS TO IMPROVE DECISION-MAKING IN PROGRESSIVE DISEASE STUDIES
S.P. Dickson, B. Haaland, C.H. Mallinckrodt, B. Dubois, P. O’Keefe, M. Morgan, O. Peters, A. Fernández Santana III, J. Harrison, A. Schneeberger, S. Hendrix
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BACKGROUND: Disease modifying therapies (DMTs) may be most beneficial in early disease, when progression is slow and changes small, with clinical relevance difficult to interpret.
OBJECTIVES: Time component tests (TCTs) translate differences between treatments from mean change, vertical distance between longitudinal trajectories, into intuitively understood time saved, horizontal distance between trajectories, which can be readily combined across endpoints in a global TCT (gTCT).
DESIGN: The value of composites, time savings estimates, and combination scores to optimize measurement and interpretation of DMTs are demonstrated, along with construction details and simulation studies.
SETTING: TCT methods were applied to a randomized phase II clinical trial.
PARTICIPANTS: Patients with early Alzheimer’s disease (N=332).
INTERVENTION: Three treatment groups with AFFITOPE® AD02 and two control groups with aluminum oxyhydroxide, AD04.
MEASUREMENTS: The co-primary efficacy outcomes were an adapted ADAS-Cog (aADAS) and adapted ADCS-ADL (aADL), which were optimized composite scales specific to cognitive and functional domains. A composite based on these two scores was the study’s prespecified primary outcome. The CDR-sb and standard non-adapted ADCS-ADL and ADAS-Cog scales were prespecified secondary outcomes.
RESULTS: The AD04 2 mg group showed some statistically significant effects compared with other study arms. It is unclear whether the observed 3.8-point difference on the composite is clinically meaningful. TCT results show a time savings of 11 months in an 18-month study with AD04 2 mg.
CONCLUSION: The relevance of 11 months saved is more universally understood than a mean difference of 3.8 points in the composite outcome. These results suggest that a combination of a composite approach and a time savings interpretation offers a powerful approach for detecting and interpreting disease modifying effects.
CITATION:
S.P. Dickson ; B. Haaland ; C.H. Mallinckrodt ; B. Dubois ; P. O’Keefe ; M. Morgan ; O. Peters ; A. Fernández Santana III ; J. Harrison ; A. Schneeberger ; S. Hendrix (2024): “Time Saved” Calculations to Improve Decision-Making in Progressive Disease Studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.64
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
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BACKGROUND: 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
MULTIOMICS BLOOD-BASED BIOMARKERS PREDICT ALZHEIMER’S PREDEMENTIA WITH HIGH SPECIFICITY IN A MULTICENTRIC COHORT STUDY
B. Souchet, A. Michaïl, M. Heuillet, A. Dupuy-Gayral, E. Haudebourg, C. Pech, A. Berthemy, F. Autelitano, B. Billoir, K. Domoto-Reilly, C. Fowler, T. Grabowski, S. Jayadev, C.L. Masters, J. Braudeau
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BACKGROUND: The primary criteria for diagnosing mild cognitive impairment (MCI) due to Alzheimer’s Disease (AD) or probable mild AD dementia rely partly on cognitive assessments and the presence of amyloid plaques. Although these criteria exhibit high sensitivity in predicting AD among cognitively impaired patients, their specificity remains limited. Notably, up to 25% of non-demented patients with amyloid plaques may be misdiagnosed with MCI due to AD, when in fact they suffer from a different brain disorder. The introduction of anti-amyloid antibodies complicates this scenario. Physicians must prioritize which amyloid-positive MCI patients receive these treatments, as not all are suitable candidates. Specifically, those with non-AD amyloid pathologies are not primary targets for amyloid-modifying therapies. Consequently, there is an escalating medical necessity for highly specific blood biomarkers that can accurately detect pre-dementia AD, thus optimizing amyloid antibody prescription.
OBJECTIVES: The objective of this study was to evaluate a predictive model based on peripheral biomarkers to identify MCI and mild dementia patients who will develop AD dementia symptoms in cognitively impaired population with high specificity.
DESIGN: Peripheral biomarkers were identified in a gene transfer-based animal model of AD and then validated during a retrospective multi-center clinical study.
SETTING: Participants from 7 retrospective cohorts (US, EU and Australia).
PARTICIPANTS: This study followed 345 cognitively impaired individuals over up to 13 years, including 193 with MCI and 152 with mild dementia, starting from their initial visits. The final diagnoses, established during their last assessments, classified 249 participants as AD patients and 96 as having non-AD brain disorders, based on the specific diagnostic criteria for each disorder subtype. Amyloid status, assessed at baseline, was available for 82.9% of the participants, with 61.9% testing positive for amyloid. Both amyloid-positive and negative individuals were represented in each clinical group. Some of the AD patients had co-morbidities such as metabolic disorders, chronic diseases, or cardiovascular pathologies.
MEASUREMENTS: We developed targeted mass spectrometry assays for 81 blood-based biomarkers, encompassing 45 proteins and 36 metabolites previously identified in AAV-AD rats.
METHODS: We analyzed blood samples from study participants for the 81 biomarkers. The B-HEALED test, a machine learning-based diagnostic tool, was developed to differentiate AD patients, including 123 with Prodromal AD and 126 with mild AD dementia, from 96 individuals with non-AD brain disorders. The model was trained using 70% of the data, selecting relevant biomarkers, calibrating the algorithm, and establishing cutoff values. The remaining 30% served as an external test dataset for blind validation of the predictive accuracy.
RESULTS: Integrating a combination of 19 blood biomarkers and participant age, the B-HEALED model successfully distinguished participants that will develop AD dementia symptoms (82 with Prodromal AD and 83 with AD dementia) from non-AD subjects (71 individuals) with a specificity of 93.0% and sensitivity of 65.4% (AUROC=81.9%, p<0.001) during internal validation. When the amyloid status (derived from CSF or PET scans) and the B-HEALED model were applied in association, with individuals being categorized as AD if they tested positive in both tests, we achieved 100% specificity and 52.8% sensitivity. This performance was consistent in blind external validation, underscoring the model’s reliability on independent datasets.
CONCLUSIONS: The B-HEALED test, utilizing multiomics blood-based biomarkers, demonstrates high predictive specificity in identifying AD patients within the cognitively impaired population, minimizing false positives. When used alongside amyloid screening, it effectively identifies a nearly pure prodromal AD cohort. These results bear significant implications for refining clinical trial inclusion criteria, facilitating drug development and validation, and accurately identifying patients who will benefit the most from disease-modifying AD treatments.
CITATION:
B. Souchet ; A. Michaïl ; M. Heuillet ; A. Dupuy-Gayral ; E. Haudebourg ; C. Pech ; A. Berthemy ; F. Autelitano ; B. Billoir ; K. Domoto-Reilly ; C. Fowler ; T. Grabowski ; S. Jayadev ; C.L. Masters ; J. Braudeau (2024): Multiomics Blood-Based Biomarkers Predict Alzheimer’s Predementia with High Specificity in a Multicentric Cohort Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.34
MENDELIAN RANDOMIZATION ANALYSIS REVEALS CAUSAL FACTORS BEHIND ALZHEIMER’S DISEASE RISK: EVIDENCE, OPPORTUNITIES, AND CHALLENGES
X. Feng, L. Zhang, Y. Hou, W. Ma, J. Ma, X. Chang, L. Yang
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Alzheimer’s disease and its comorbidities pose a heavy disease burden globally, and its treatment remains a major challenge. Identifying the protective and risk factors for Alzheimer’s disease, as well as its possible underlying molecular processes, can facilitate the development of interventions that can slow its progression. Observational studies and randomized controlled trials have provided some evidence regarding potential risk factors for Alzheimer’s disease; however, the results of these studies vary. Mendelian randomization is a novel epidemiological methodology primarily used to infer causal relationships between exposures and outcomes. Many Mendelian randomization studies have identified potential causal relationships between Alzheimer’s disease and certain diseases, lifestyle habits, and biological exposures, thus providing valuable data for further mechanistic studies and the development and implementation of clinical prevention strategies. However, the results and data from Mendelian randomization studies must be interpreted based on comprehensive evidence. Moreover, the existing Mendelian randomization studies on the epidemiology of Alzheimer’s disease have some limitations that are worth exploring. Therefore, the aim of this review was to summarize the available evidence on the potential protective and risk factors for Alzheimer’s disease by assessing published Mendelian randomization studies on Alzheimer’s disease, and to provide new perspectives on the etiology of Alzheimer’s disease.
CITATION:
X. Feng ; L. Zhang ; Y. Hou ; W. Ma ; J. Ma ; X. Chang ; L. Yang ; (2024): Mendelian Randomization Analysis Reveals Causal Factors behind Alzheimer’s Disease Risk: Evidence, Opportunities, and Challenges. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.30
POLYGENIC RISK SCORE REVEALS GENETIC HETEROGENEITY OF ALZHEIMER’S DISEASE BETWEEN THE CHINESE AND EUROPEAN POPULATIONS
F. Li, S. Xie, J. Cui, Y. Li, T. Li, Y. Wang, J. Jia
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BACKGROUND: The polygenic risk score (PRS) aggregates the effects of numerous genetic variants associated with a condition across the human genome and may help to predict late-onset Alzheimer’s disease (LOAD). Most of the current PRS studies on Alzheimer’s disease (AD) have been conducted in Caucasian ancestry populations, while it is less studied in Chinese.
OBJECTIVE: To establish and examine the validity of Chinese PRS, and explore its racial heterogeneity.
DESIGN: We constructed a PRS using both discovery (N = 2012) and independent validation samples (N = 1008) from Chinese population. The associations between PRS and age at onset of LOAD or cerebrospinal fluid (CSF) biomarkers were assessed. We also replicated the PRS in an independent replication cohort with CSF data and constructed an alternative PRS using European weights.
SETTING: Multi-center genetics study.
PARTICIPANTS: A total of 3020 subjects were included in the study.
MEASUREMENTS: PRS was calculated using genome-wide association studies data and evaluated the performance alone (PRSnoAPOE) and with other predictors (full model: LOAD ~ PRSnoAPOE + APOE+ sex + age) by measuring the area under the receiver operating curve (AUC).
RESULTS: PRS of the full model achieved the highest AUC of 84.0% (95% CI = 81.4-86.5) with pT< 0.5, compared with the model containing APOE alone (61.0%). The AUC of PRS with pT< 5e-8 was 77.8% in the PRSnoAPOE model, 81.5% in the full model, and only ranged from 67.5% to 75.1% in the PRS with the European weights model. A higher PRS was significantly associated with an earlier age at onset (P <0.001). The PRS also performed well in the replication cohort of the full model (AUC=83.1%, 95% CI = 74.3-92.0). The CSF biomarkers of Aβ42 and the ratio of Aβ42/Aβ40 were significantly inversely associated with the PRS, while p-Tau181 showed a positive association.
CONCLUSIONS: This finding suggests that PRS reveal genetic heterogeneity and higher prediction accuracy of the PRS for AD can be achieved using a base dataset and validation within the same ethnicity. The effective PRS model has the clinical potential to predict individuals at risk of developing LOAD at a given age and with abnormal levels of CSF biomarkers in the Chinese population.
CITATION:
F. Li ; S. Xie ; J. Cui ; Y. Li ; T. Li ; Y. Wang ; J. Jia (2024): Polygenic Risk Score Reveals Genetic Heterogeneity of Alzheimer’s Disease between the Chinese and European Populations. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.29
INVESTIGATING THE IMPACT OF TEA CONSUMPTION ON COGNITIVE FUNCTION AND EXPLORING TEA-GENETIC INTERACTIONS IN OLDER ADULTS AGED 65-105 YEARS: FINDINGS FROM THE 2002−2018 CLHLS DATA
L. Yu, M. Yang, K.X. Ye, C. Li, M. Zou, J. Wang, X. Yuan, D. Zheng, C. Sun, Y. Zhang, Q. Feng, A.B. Maier, L. Sun, L. Feng, Y. Wang, H. Chen, Y. Zeng
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BACKGROUND: As the global population ages, cognitive impairment (CI) becomes more prevalent. Tea has been one of the most popular drinks in the world. Several studies have demonstrated that tea consumption has an impact on cognitive function.
OBJECTIVE: This study aims to examine the association between tea consumption and cognitive function and explore the potential effect of genetics on the relationship between tea consumption and CI risk in older adults.
DESIGN: This is a prospective longitudinal study using data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS).
SETTING: Six waves of data from CLHLS containing 76,270 subjects were analyzed. Generalized estimation equations (GEE) with a logit link function were adopted to estimate the effect of tea consumption on CI risk from a cross-sectional and longitudinal perspective.
PARTICIPANTS: A population-based cohort of adults aged 65-105 years.
MEASUREMENTS: The frequency and type of tea consumption were obtained by questionnaires. CI was measured based on MMSE. Polygenic risk was measured using the polygenic score approach described by the International Schizophrenia.
RESULTS: The results showed that drinking green tea had a better protective effect on cognitive function than other types of tea, the incidence of CI gradually decreased with the increase of tea consumption frequency, and men were more likely to benefit from tea consumption. Additionally, we also found a significant interaction between tea consumption and genetic risk, measured by polygenic risk score (PRS).
CONCLUSIONS: Based on current research evidence, tea consumption, may be a simple and important measure for CI prevention.
CITATION:
L. Yu ; M. Yang ; K.X. Ye ; C. Li ; M. Zou ; J. Wang ; X. Yuan ; D. Zheng ; C. Sun ; Y. Zhang ; Q. Feng ; A.B. Maier ; L. Sun ; L. Feng ; Y. Wang ; H. Chen ; Y. Zeng (2024): Investigating the Impact of Tea Consumption on Cognitive Function and Exploring Tea-Genetic Interactions in Older Adults Aged 65-105 Years: Findings from the 2002−2018 CLHLS Data. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.22
EDUCATION AS RISK FACTOR OF MILD COGNITIVE IMPAIRMENT: THE LINK TO THE GUT MICROBIOME
M. Klee, V.T.E. Aho, P. May, A. Heintz-Buschart, Z. Landoulsi, S.R. Jónsdóttir, C. Pauly, L. Pavelka, L. Delacour, A. Kaysen, R. Krüger, P. Wilmes, A.K. Leist, on behalf of the NCER-PD Consortium
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BACKGROUND: With differences apparent in the gut microbiome in mild cognitive impairment (MCI) and dementia, and risk factors of dementia linked to alterations of the gut microbiome, the question remains if gut microbiome characteristics may mediate associations of education with MCI.
OBJECTIVES: We sought to examine potential mediation of the association of education and MCI by gut microbiome diversity or composition.
DESIGN: Cross-sectional study.
SETTING: Luxembourg, the Greater Region (surrounding areas in Belgium, France, Germany).
PARTICIPANTS: Control participants of the Luxembourg Parkinson’s Study.
MEASUREMENTS: Gut microbiome composition, ascertained with 16S rRNA gene amplicon sequencing. Differential abundance, assessed across education groups (0-10, 11-16, 16+ years of education). Alpha diversity (Chao1, Shannon and inverse Simpson indices). Mediation analysis with effect decomposition was conducted with education as exposure, MCI as outcome and gut microbiome metrics as mediators.
RESULTS: After exclusion of participants below 50, or with missing data, n=258 participants (n=58 MCI) were included (M [SD] Age=64.6 [8.3] years). Higher education (16+ years) was associated with MCI (Odds ratio natural direct effect=0.35 [95% CI 0.15-0.81]. Streptococcus and Lachnospiraceae-UCG-001 genera were more abundant in higher education.
CONCLUSIONS: Education is associated with gut microbiome composition and MCI risk without clear evidence for mediation. However, our results suggest signatures of the gut microbiome that have been identified previously in AD and MCI to be reflected in lower education and suggest education as important covariate in microbiome studies.
CITATION:
M. Klee ; V.T.E. Aho ; P. May ; A. Heintz-Buschart ; Z. Landoulsi ; S.R. Jónsdóttir ; C. Pauly ; L. Pavelka ; L. Delacour ; A. Kaysen ; R. Krüger ; P. Wilmes ; A.K. Leist ; on behalf of the NCER-PD Consortium ; (2024): Education as Risk Factor of Mild Cognitive Impairment: The Link to the Gut Microbiome. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.19
ASSOCIATION OF VASCULAR ENDOTHELIAL GROWTH FACTOR LEVELS WITH RISK OF ALZHEIMER’S DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS
S.S. Zakariaee, N. Naderi, E. Azizi
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BACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative illness that leads to impairment of cognitive functions and memory loss. Even though there is a plethora of research reporting the abnormal regulation of VEGF expression in AD pathogenesis, whether the CSF and serum VEGF are increased in AD is an open question yet. In this study, the association of CSF and serum VEGF concentrations with the risk of Alzheimer’s disease was investigated using systematic review and meta-analysis.
METHODS: A systematic literature search was carried out using online specialized biomedical databases of Web of Science, Pubmed, Scopus, Embase, and Google Scholar until Feb 2023 without restriction to the beginning time. The meta-analysis was performed using the random-effects model and only case-control publications describing VEGF concentrations in Alzheimer’s patients were considered for calculating the pooled effect size.
RESULTS: In the systematic literature search, 6 and 13 studies met the inclusion criteria to evaluate CSF and serum VEGF concentrations of Alzheimer’s patients, respectively. This meta-analysis retrieved a total number of 2380 Alzheimer’s patients and 5368 healthy controls. Under the random-effects model in the meta-analysis, the pooled SMD for CSF and serum VEGF concentrations of Alzheimer’s patients were -0.13 (95%CI,-0.42–0.16) and 0.23 (95%CI,-0.27–0.73), respectively. Results of meta-regression analysis showed that the quality scores of papers and female sex ratios of participants did not affect the associations of VEGF concentrations with the risk of Alzheimer’s disease. However, the age average of patients significantly affects the associations of CSF VEGF concentrations with the risk of Alzheimer’s disease (P=0.051). There was a statistically significant subgroup effect for the disease severity of Alzheimer’s patients which modifies the associations of serum VEGF concentrations with the risk of Alzheimer’s disease (P<0.01) and subgroup analysis shows that study location modifies the associations of CSF and serum VEGF concentrations with the risk of Alzheimer’s disease (P<0.01).
CONCLUSION: The results show that the serum VEGF concentrations increased for Alzheimer’s patients in accordance with the increased expression of VEGF and the VEGF levels of Alzheimer’s patients decreased by increasing their disease severities. Therefore, in addition to detecting AD in the earliest stages of the disease, serum VEGF could be a promising biomarker to follow up on the disease and evaluate the clinical course of the disease.
CITATION:
S.S. Zakariaee ; N. Naderi ; E. Azizi (2024): Association of Vascular Endothelial Growth Factor Levels with Risk of Alzheimer’s Disease: A Systematic Review and Meta-Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.18
JPAD Volume 11, N°02 - 2024
ANTI-AMYLOID THERAPIES FOR ALZHEIMER’S DISEASE: AN ALZHEIMER EUROPE POSITION PAPER AND CALL TO ACTION
A.C. Bradshaw, J. Georges, on behalf of the Alzheimer Europe Board
J Prev Alz Dis 2024;2(11):265-273
Show summaryHide summaryThe growing prevalence and burden of Alzheimer’s disease has catalysed huge investments in research on its causes, diagnosis, treatment and care. After many high-profile failures, recent clinical trials of anti-amyloid drugs have marked a turning point for the field, leading to the approval of the first disease-modifying therapies for Alzheimer’s disease by the FDA. It is now up to European regulators to determine whether there is sufficient evidence to approve these drugs for patients with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Here, we outline Alzheimer Europe’s position on anti-amyloid therapies for Alzheimer’s disease, which was adopted by the Board of Alzheimer Europe following consultations with our member associations and with the European Working Group of People with Dementia. Beyond questions of drug efficacy, safety and cost, we highlight important issues that must be addressed by industry, regulators, payers, healthcare systems and governments, to ensure that patients have timely, appropriate and equitable access to innovative treatments, regardless of their socio-economic background, insurance status, or place of residence. We also call for continued investment in research on treatments that might benefit people with more advanced Alzheimer’s disease – as well as support and care services that can help people live well with dementia at all stages of the disease.
CITATION:
A.C. Bradshaw ; J. Georges ; on behalf of the Alzheimer Europe Board ; (2024): Anti-Amyloid Therapies for Alzheimer’s Disease: An Alzheimer Europe Position Paper and Call to Action. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.37
ETHICAL CONSIDERATIONS AT THE INTERSECTION OF SOCIAL MEDIA AND DEMENTIA PREVENTION RESEARCH
V. Hrincu, G. Zaleski, J.M. Robillard
J Prev Alz Dis 2024;2(11):274-284
Show summaryHide summaryonline engagement for dementia prevention research. Existing social media guidelines are broad and lack empirical justification reflecting the values and priorities of the dementia community and the challenges specific to prevention research.
OBJECTIVES: By engaging professional and community experts, we sought to identify the ethical issues, motivators, and barriers pertaining to social media engagement for dementia prevention research.
DESIGN: Semi-structured, qualitative interviews conducted online.
SETTING: We recruited participants using a combination of accessible online databases, advertisements/posters through organizational newsletters and websites, social media, registries, and from our network of colleagues.
PARTICIPANTS: Professional experts working in dementia research (n=15; e.g., researchers, coordinators) and experts with lived experience (n=14). Experts were from Canada, the USA, the UK, and Chile.
MEASUREMENTS: Discussions were analyzed using thematic qualitative analysis methods.
RESULTS: Professional experts revealed a dearth of social media guidelines for prevention research, relying on informal sources to supplement ethics board approval. They sought methods of strategic communication for public dialogue (e.g., misinformation, criticism). Experts by experience appreciated the educational benefits of social media but raised risks such as diminished online privacy, dementia-related stigma, being targeted for predatory practices, and misinformation. Various digital inequities (e.g., age, socioeconomic status) dampen social media’s reach to diverse publics. Participants acknowledged that younger aging populations have more digital fluency and may benefit more from social media research engagement.
CONCLUSIONS: Research professionals and community members identified ethical and contextual factors surrounding the use of social media for dementia prevention, and a need for more guidance. The next project phase will use these data to inform the co-creation of ethical guidelines for brain health research.
CITATION:
V. Hrincu ; G. Zaleski ; J.M. Robillard ; (2024): Ethical Considerations at the Intersection of Social Media and Dementia Prevention Research. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.4
ALZHEIMER’S DISEASE BIOMARKER DECISION-MAKING AMONG PATIENTS WITH MILD COGNITIVE IMPAIRMENT AND THEIR CARE PARTNERS
C.G. Cox, C.R. Salazar, A.I. Birnbaum, M. Witbracht, S.P. Tam, G.T. Thai, S.A. Sajjadi, D.L. Gillen, J.D. Grill
J Prev Alz Dis 2024;2(11):285-293
Show summaryHide summaryBAKGROUND Alzheimer’s disease (AD) biomarker tests can be ordered as part of the diagnostic workup of patients with mild cognitive impairment (MCI). Little is known about how patients with MCI and their care partners decide whether to pursue testing.
OBJECTIVE: To examine factors that influence AD biomarker testing decisions among patients with MCI and their care partners.
DESIGN: We performed structured research interviews with patients with MCI and their study partners to assess the importance of eight factors in the decision whether to undergo AD biomarker testing (6-point Likert scale; 1-extremely unimportant to 6-extremely important): cost, fear of testing procedures, learning if AD is the cause of cognitive problems, concern about health insurance, instructing future planning, informing treatment decisions, family members’ opinions, and doctor recommendation.
SETTING: Two researchers administered interviews with participants in-person (i.e., participant home, research center) or remotely (i.e., telephone, video-conference).
PARTICIPANTS: We completed interviews with 65 patients with a diagnosis of MCI and 57 study partners, referred by dementia specialist clinicians from the University of California, Irvine health system.
MEASUREMENTS: We used generalized estimating equations (GEE) to examine the mean importance of each factor among patients and study partners, and the mean difference in importance of each factor within dyads.
RESULTS: One third of participants reported the patient had previously undergone AD biomarker testing. Fifty-five percent of patients and 65% of study partners who reported no previous testing indicated a desire for the patient to be tested. GEE analyses found that patients and study partners rated the following factors with highest importance: informing treatment decisions (mean score 5.29, 95% CI: 5.06, 5.52 for patients; mean score 5.56, 95% CI: 5.41, 5.72 for partners); doctor recommendation (4.94, 95% CI: 4.73, 5.15 for patients; 5.16, 95% CI: 4.97, 5.34 for partners); and instructing future planning (4.88, 95% CI: 4.59, 5.16 for patients; 5.11, 95% CI: 4.86, 5.35 for partners). High dyadic agreement was observed for all factors except fear of testing, which patients rated with lower importance than their study partners.
CONCLUSIONS Biomarker testing for AD in patients with MCI is a rapidly evolving practice and limited data exist on patient perspectives. In this study, most patients and their care partners were interested in testing to help inform treatment decisions and to plan for the future. Participants placed high importance on clinician recommendations for biomarker testing, highlighting the need for clear communication and education on the options, limitations, risks, and benefits of testing.
CITATION:
C.G. Cox ; C.R. Salazar ; A.I. Birnbaum ; M. Witbracht ; S.P. Tam ; G.T. Thai ; S.A. Sajjadi ; D.L. Gillen ; J.D. Grill ; (2024): Alzheimer’s Disease Biomarker Decision-Making among Patients with Mild Cognitive Impairment and Their Care Partners. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.10
A PRAGMATIC, INVESTIGATOR-DRIVEN PROCESS FOR DISCLOSURE OF AMYLOID PET SCAN RESULTS TO ADNI-4 RESEARCH PARTICIPANTS
C.M. Erickson, J. Karlawish, J.D. Grill, K. Harkins, S.M. Landau, M.G. Rivera-Mindt, O. Okonkwo, R.C. Petersen, P.S. Aisen, M.W. Weiner, E.A. Largent
J Prev Alz Dis 2024;2(11):294-302
Show summaryHide summaryBACKGROUND: Prior studies of Alzheimer’s disease (AD) biomarker disclosure have answered important questions about individuals’ safety after learning and comprehending their amyloid PET results; however, these studies have typically employed highly structured disclosure protocols and focused on the psychological impact of disclosure (e.g., anxiety, depression, and suicidality) in homogeneous populations. More work is needed to develop flexible disclosure protocols and study outcomes in ethnoculturally representative samples.
METHODS: The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is formally incorporating amyloid PET disclosure into the newest protocol (ADNI-4). Participants across the cognitive spectrum who wish to know their amyloid PET results may learn them. The pragmatic disclosure process spans four timepoints: (1) a pre-disclosure visit, (2) the PET scan and its read, (3) a disclosure visit, and (4) a post-disclosure check-in. This process applies to all participants, with slight modifications to account for their cognitive status. In designing this process, special emphasis was placed on utilizing investigator discretion. Participant measures include perceived risk of dementia, purpose in life, and disclosure satisfaction. Investigator assessment of the disclosure visit (e.g., challenges encountered, topics discussed, etc.) is also included.
RESULTS: Data collection is ongoing. Results will allow for more robust characterization of the impact of learning amyloid PET results on individuals and describe the perspectives of investigators.
CONCLUSION: The pragmatic design of the disclosure process in ADNI-4 coupled with the novel participant and investigator data will inform future disclosure practices. This is especially important as disclosure of biomarker results expands in research and care.
CITATION:
C.M. Erickson ; J. Karlawish ; J.D. Grill ; K. Harkins ; S.M. Landau ; M.G. Rivera-Mindt ; O. Okonkwo ; R.C. Petersen ; P.S. Aisen ; M.W. Weiner ; E.A. Largent ; (2024): A Pragmatic, Investigator-Driven Process for Disclosure of Amyloid PET Scan Results to ADNI-4 Research Participants. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.33
HEALTH ECONOMIC CONSIDERATIONS IN THE DEPLOYMENT OF AN ALZHEIMER’S PREVENTION THERAPY
S. Mattke, H. Jun, M. Hanson, S. Chu, J.H. Kordower, E.M. Reiman
J Prev Alz Dis 2024;2(11):303-309
Show summaryHide summaryINTRODUCTION: As treatments for secondary prevention of Alzheimer’s disease (AD) are being studied, concerns about their value for money have appeared. We estimate cost-effectiveness of a hypothetical screening and prevention program.
METHODS: We use a Markov model to project cost-effectiveness of a treatment that reduces progression to symptomatic AD by 50% with either chronic treatment until progression to mild cognitive impairment or treatment for one year followed by monitoring with AD blood tests and retreatment with one dose in case of amyloid re-accumulation. Diagnoses would be made with an AD blood test with sensitivity and specificity of 80%, and inconclusive results in 20%. Individuals testing negative would be re-tested in five years and those with inconclusive results in one.
RESULTS: The program would generate per-person value of $53,721 from a payer (reduction of direct cost and patient QALY gains) and $69,861 from a societal perspective (adding valuation of reduced caregiver burden). With chronic treatment, it would be cost-effective up to annual drug prices of $7,000 and $10,300, respectively. Time-limited treatment would be cost-effective at annual drug prices of $54,257 and $78,458 from a payer and societal perspective, respectively. Higher specificity of the blood test would decrease cost per person with similar value generation
DISCUSSION: A hypothetical prevention treatment for AD could be economically viable from a payer and societal perspective.
CITATION:
S. Mattke ; H. Jun ; M. Hanson ; S. Chu ; J.H. Kordower ; E.M. Reiman ; (2024): Health Economic Considerations in the Deployment of an Alzheimer’s Prevention Therapy. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.23
POTENTIAL IMPLICATIONS OF SLOWING DISEASE PROGRESSION IN AMYLOID-POSITIVE EARLY ALZHEIMER’S DISEASE: ESTIMATES FROM REAL-WORLD DATA
J. Chandler, N. Done, U. Desai, M. Georgieva, A. Gomez-Lievano, W. Ye, A. Zhao, D. Eid, A. Hilts, N. Kirson, T. Schilling, for the Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2024;2(11):310-319
Show summaryHide summaryBACKGROUND: Emerging therapies have shown promising results for slowing the progression of Alzheimer’s disease (AD). However, the potential impact of these therapies on real-world outcomes remains to be explored.
OBJECTIVE: To examine the impact of slowing AD progression on functional abilities and behavioral symptoms.
DESIGN: Retrospective observational study.
SETTING: Data from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) in the United States (06/2005-11/2021, primary analysis) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (09/2005-03/2022, sensitivity analysis) were used.
PARTICIPANTS: Individuals with mild cognitive impairment (MCI) or mild dementia, Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score 0.5-9.0 (inclusive; first visit defined as the index date), and confirmed amyloid positivity were identified in NACC. In ADNI, individuals with at least one clinical center visit with a clinical assessment of MCI or mild dementia and confirmed amyloid positivity were identified.
MEASUREMENTS: Hypothetical effects of slowing disease progression as assessed by CDR-SB on functional and behavioral outcomes including the Functional Activities Questionnaire (FAQ) score, Neuropsychiatric Inventory Questionnaire (NPI-Q) score, and the probability of complete dependence over five years were evaluated using multivariable regression among NACC participants, separately for the subgroups with MCI and mild dementia at baseline, respectively. For the ADNI sensitivity analysis, the hypothetical effects of slowing disease progression were evaluated for FAQ score using multivariable regression among the MCI participants only.
RESULTS: Compared with natural disease progression, slowing progression by 20% over five years for NACC participants with MCI and mild dementia, respectively, would result in 1.7-point (10.8%) and 1.6-point (12.9%) less deterioration based on FAQ; 0.5-point (20.3%) and 0.5-point (19.3%) less deterioration based on NPI-Q; 4.7 percentage-point (22.2%) and 10.1 percentage-point (21.6%) lower probability of complete dependence. Among ADNI participants, delaying disease progression by 20% or 30% over 4 years would avert deterioration based on FAQ of 1.1 points (20.4%) and 1.6 points (29.6%), respectively, compared to natural disease progression.
CONCLUSIONS: Slowing early AD progression could result in preservation of functional and behavioral attributes and functional autonomy for longer.
CITATION:
J. Chandler ; N. Done ; U. Desai ; M. Georgieva ; A. Gomez-Lievano ; W. Ye ; A. Zhao ; D. Eid ; A. Hilts ; N. Kirson ; T. Schilling ; for the Alzheimer’s Disease Neuroimaging Initiative ; (2024): Potential Implications of Slowing Disease Progression in Amyloid-Positive Early Alzheimer’s Disease: Estimates from Real-World Data. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.27
IMPACT OF DIFFERENTIAL RATES OF DISEASE PROGRESSION IN AMYLOID-POSITIVE EARLY ALZHEIMER’S DISEASE: FINDINGS FROM A LONGITUDINAL COHORT ANALYSIS
J. Chandler, M. Georgieva, U. Desai, N. Done, A. Gomez-Lievano, W. Ye, A. Zhao, D. Eid, A. Hilts, N. Kirson, T. Schilling
J Prev Alz Dis 2024;2(11):320-328
Show summaryHide summaryBACKGROUND: There is limited literature regarding the impact of differential rates of disease progression on longitudinal outcomes in individuals with early Alzheimer’s disease (AD) and confirmed brain amyloid pathology.
OBJECTIVES: To describe the underlying characteristics and long-term outcomes associated with different rates of disease progression among amyloid-positive individuals with early symptomatic AD.
DESIGN: Retrospective observational study.
SETTING: Data from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) in the United States (06/2005-11/2021).
PARTICIPANTS: Individuals with a clinical assessment of mild cognitive impairment or dementia and Clinical Dementia Rating® Dementia Staging Instrument Sum of Boxes (CDR-SB) score 0.5-9.0 (inclusive; first visit defined as the index date) and confirmed amyloid positivity. Participants were stratified into No Progression (change ≤0), Slower Progression (0< change <2.0 points), Median Progression (2.0-point change), and Faster Progression (change >2.0 points) cohorts based on the observed distribution of changes in CDR-SB score between the index and first subsequent visit.
MEASUREMENTS: For each cohort, the functional and neuropsychiatric outcomes were described at index and each subsequent visit for up to five years, and least-square (LS) mean changes from baseline were estimated using linear mixed-effects models adjusting for baseline demographic and clinical characteristics.
RESULTS: Among 1,263 participants included in the analysis, the mean±standard deviation (SD) age at index was 72.7±9.7 years and 55.3% were males. Demographic characteristics and comorbidity profiles at index were similar across cohorts. However, at index, the Faster Progression (N=279) cohort had higher CDR-SB and Functional Assessment Questionnaire (FAQ) scores compared with the No Progression (N=474), Slower Progression (N=297), and Median Progression (N=213) cohorts. Adjusting for baseline characteristics, at year 5 after index the FAQ score increased by 23.6 points for Faster Progression cohort and 10.4, 15.8, and 19.2 points for the No, Slower, and Median Progression cohorts, respectively. The corresponding increases in Neuropsychiatric Inventory Questionnaire (NPI-Q) scores were 6.7 points for the Faster Progression cohort, and by 1.3, 3.1, and 8.3 points, for the No, Slower, and Median Progression cohorts, respectively.
CONCLUSIONS: Despite similar demographic and clinical profiles at baseline, amyloid-positive individuals with greater deterioration based on CDR-SB early in the AD trajectory continue to experience worse functional and behavioral outcomes over time than those with more gradual deterioration in this metric.
CITATION:
J. Chandler ; M. Georgieva ; U. Desai ; N. Done ; A. Gomez-Lievano ; W. Ye ; A. Zhao ; D. Eid ; A. Hilts ; N. Kirson ; T. Schilling ; (2024): Impact of Differential Rates of Disease Progression in Amyloid-Positive Early Alzheimer’s Disease: Findings from a Longitudinal Cohort Analysis . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.28
VALIDATION, DEPLOYMENT, AND REAL-WORLD IMPLEMENTATION OF A MODULAR TOOLBOX FOR ALZHEIMER’S DISEASE DETECTION AND DEMENTIA RISK REDUCTION: THE AD-RIDDLE PROJECT
K. Malzbender, P. Barbarino, P. Barkman Ferrell, A. Bradshaw, A.J. Brookes, C. Díaz, W.M. van der Flier, J. Georges, O. Hansson, M. Hartmanis, L. Jönsson, R. Krishnan, T. MacLeod, F. Mangialasche, P. Mecocci, C. Minguillon, L. Middleton, S. Pla, S.P. Sardi, M. Schöll, M. Suárez-Calvet, W. Weidner, P.J. Visser, H. Zetterber, N. Bose, A. Solomon, M. Kivipelto, on behalf of the AD-RIDDLE Consortium
J Prev Alz Dis 2024;2(11):329-338
Show summaryHide summaryThe Real-World Implementation, Deployment, and Validation of Early Detection Tools and Lifestyle Enhancement (AD-RIDDLE) project, recently launched with the support of the EU Innovative Health Initiative (IHI) public-private partnership and UK Research and Innovation (UKRI), aims to develop, test, and deploy a modular toolbox platform that can reduce existing barriers to the timely detection, and therapeutic approaches in Alzheimer’s disease (AD), thus accelerating AD innovation. By focusing on health system and health worker practices, AD-RIDDLE seeks to improve and smooth AD management at and between each key step of the clinical pathway and across the disease continuum, from at-risk asymptomatic stages to early symptomatic ones. This includes innovation and improvement in AD awareness, risk reduction and prevention, detection, diagnosis, and intervention. The 24 partners in the AD-RIDDLE interdisciplinary consortium will develop and test the AD-RIDDLE toolbox platform and its components individually and in combination in six European countries. Expected results from this cross-sectoral research collaboration include tools for earlier detection and accurate diagnosis; validated, novel digital cognitive and blood-based biomarkers; and improved access to individualized preventative interventions (including multimodal interventions and symptomatic/disease-modifying therapies) across diverse populations, within the framework of precision medicine. Overall, AD-RIDDLE toolbox platform will advance management of AD, improving outcomes for patients and their families, and reducing costs.
CITATION:
K. Malzbender ; P. Barbarino ; P. Barkman Ferrell ; A. Bradshaw ; A.J. Brookes ; C. Díaz ; W.M. van der Flier ; J. Georges ; O. Hansson ; M. Hartmanis ; L. Jönsson ; R. Krishnan ; T. MacLeod ; F. Mangialasche ; P. Mecocci ; C. Minguillon ; L. Middleton ; S. Pla ; S.P. Sardi ; M. Schöll ; M. Suárez-Calvet ; W. Weidner ; P.J. Visser ; H. Zetterberg ; N. Bose ; A. Solomon ; M. Kivipelto ; on behalf of the AD-RIDDLE Consortium ; (2024): Validation, Deployment, and Real-World Implementation of a Modular Toolbox for Alzheimer’s Disease Detection and Dementia Risk Reduction: The AD-RIDDLE Project. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.32
EXPLORING THE ASSOCIATION BETWEEN AMYLOID-Β AND MEMORY MARKERS FOR ALZHEIMER’S DISEASE IN COGNITIVELY UNIMPAIRED OLDER ADULTS
M.A. Parra, Y. Gazes, C. Habeck, Y. Stern
J Prev Alz Dis 2024;2(11):339-347
Show summaryHide summaryBACKGROUND: Memory tests vary in their sensitivity for detection of pre-symptomatic Alzheimer’s disease (AD). The Visual Short-Term Memory Binding Test (VSTMBT) identifies AD-related performance deficits in older adults who are otherwise cognitively unimpaired.
OBJECTIVE: We investigated the association of this psychometric measure with brain amyloidosis and atrophy.
DESIGN: Cross-sectional mixed and correlational.
SETTING: Cognitive Reserve Study from Columbia University.
PARTICIPANTS: a sample of 39 cognitively unimpaired older adults (Age: M=65.3, SD=3.07) was obtained from the above study.
MEASUREMENTS: Extensive neuropsychological and neuroimaging (MRI and amyloid-β PET) assessments were carried out.
RESULTS: Performance on the VSTMBT allowed us to split the sample into Low Binding Cost (LBC, N=21) and High Binding Cost (HBC, N=18). Groups were matched according to age [p=0.702], years of education [0.071], and sex [p=0.291]. HBC’s performance was comparable to that seen in symptomatic AD. Groups only differed in their amyloid-β deposition on PET in regions of the right ventral stream linked to visual cognition and affected early in AD pathogenesis (lateral-occipital cortex, p = 0.008; fusiform gyrus, p = 0.017; and entorhinal cortex, p = 0.046). Other regions known to be linked to low-level visual integration function also revealed increased amyloid-β deposition in HBC.
CONCLUSIONS: VSTMB deficits are associated with neuropathogenesis (i.e., amyloid-β deposition) in the earliest affected regions in pre-symptomatic AD. The VSTMB test holds potential for the identification of cognitively unimpaired older adults with very early AD pathogenesis and may thus be a useful tool for early intervention trials or other forms of clinical research.
CITATION:
M.A. Parra ; Y. Gazes ; C. Habeck ; Y. Stern ; (2024): Exploring the Association between Amyloid-β and Memory Markers for Alzheimer’s Disease in Cognitively Unimpaired Older Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.11
WHO BENEFITED THE MOST? EFFECTIVENESS OF A LIFESTYLE INTERVENTION AGAINST COGNITIVE DECLINE IN OLDER WOMEN AND MEN – SECONDARY ANALYSIS OF THE AGEWELL. DE-TRIAL
F.G. Wittmann, A. Pabst, A. Zülke, M. Luppa, I. Blotenberg, M.I. Cardona, A. Bauer, S. Fuchs, I. Zöllinger, L. Sanftenberg, C. Brettschneider, J. Döhring, L. Lunden, D. Czock, B. Wiese, J.R. Thyrian, W. Hoffmann, T. Frese, J. Gensichen, H.-H. König, H. Kaduszkiewicz, S.G. Riedel-Heller
J Prev Alz Dis 2024;2(11):348-355
Show summaryHide summaryINTRODUCTION: Differences between women and men matter in the prevalence and risk factors of dementia. We aimed to examine potential sex differences regarding the effectiveness by running a secondary analysis of the AgeWell.de trial, a cluster-randomized multicenter multi-domain lifestyle intervention to reduce cognitive decline.
METHODS: Intention-to-treat analyses of women (n=433) and men (n=386) aged 60 to 77 years were used for models including interactions between intervention group allocation and sex followed by subgroup analysis stratified by sex on primary and secondary outcomes. Further, the same procedure was repeated for age groups (60-69 vs. 70-77) within sex-specific subgroups to assess the effectiveness in different age groups. Trial registration: German Clinical Trials Register (ref. number: DRKS00013555).
RESULTS: No differences were found between women and men in the effectiveness of the intervention on cognitive performance. However, women benefitted from the intervention regarding depressive symptoms while men did not. Health-related quality of life was enhanced for younger intervention participants (60-69 years) in both women and men.
CONCLUSION: The AgeWell.de intervention was able to improve depressive symptoms in women and health-related quality of life in younger participants. Female participants between 60 and 69 years benefited the most. Results support the need of better individually targeted lifestyle interventions for older adults.
CITATION:
F.G. Wittmann ; A. Pabst ; A. Zülke ; M. Luppa ; I. Blotenberg ; M.I. Cardona ; A. Bauer ; S. Fuchs ; I. Zöllinger ; L. Sanftenberg ; C. Brettschneider ; J. Döhring ; L. Lunden ; D. Czock ; B. Wiese ; J.R. Thyrian ; W. Hoffmann ; T. Frese ; J. Gensichen ; H.-H. König ; H. Kaduszkiewicz ; S.G. Riedel-Heller (2024): Who Benefited the Most? Effectiveness of a Lifestyle Intervention Against Cognitive Decline in Older Women and Men – Secondary Analysis of the AgeWell.de-trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.13
ROLES OF BASELINE INTRINSIC CAPACITY AND ITS SUBDOMAINS ON THE OVERALL EFFICACY OF MULTIDOMAIN INTERVENTION IN PROMOTING HEALTHY AGING AMONG COMMUNITYDWELLING OLDER ADULTS: ANALYSIS FROM A NATIONWIDE CLUSTER-RANDOMIZED CONTROLLED TRIAL
C.-K. Liang, W.-J. Lee, M.-Y. Chou, A.-C. Hwang, C.-S. Lin, L.-N. Peng, F.-Y. Hsiao, C.-H. Loh, L.-K. Chen
J Prev Alz Dis 2024;2(11):356-365
Show summaryHide summaryBackground: Impaired intrinsic capacity (IC), which affects approximately 90% of older adults, is associated with a significantly heightened risk of frailty and cognitive decline. Existing evidence suggests that multidomain interventions have the potential to enhance cognitive performance and yield positive effects on physical frailty.
OBJECTIVE: To examine roles of baseline IC and its subdomains on the efficacy of multidomain interventions in promoting healthy aging in older adults.
DESIGN: a cluster-randomized controlled trial.
Setting and Participants: 1,054 community-dwelling older adults from 40 community-based clusters across Taiwan.
INTERVENTION: A 12-month pragmatic multidomain intervention of exercise, cognitive training, nutritional counseling and chronic condition management.
MEASUREMENTS: Baseline IC was measured by 5 subdomains, including cognition (Montreal Cognitive Assessment, MoCA), sensory (visual and hearing impairment), vitality (handgrip strength or Mini-Nutritional Assessment-short form), psychological well-being (Geriatric Depression Scale-5), and locomotion (6m gait speed). Outcomes of interest were cognitive performance (MoCA scores) and physical frailty (CHS frailty score) over a follow-up period of 6 and 12 months.
RESULTS: Of all participants (mean age:75.1±6.4 years, 68.6% female), about 90% participants had IC impairment at baseline (2.0±1.2 subdomains). After covariate adjustment using a generalized linear mixed model (GLMM), the multidomain intervention significantly prevented cognitive declines and physical frailty, particularly in those with IC impairment ≥ 3 subdomains (MoCA: coefficient: 1.909, 95% CI: 0.736 ~ 3.083; CHS frailty scores: coefficient = -0.405, 95% CI: -0.715 ~ -0.095). To assess the associations between baseline poor capacity in each IC subdomain and MoCA/CHS frailty scores over follow-up, a 3-way interaction terms (time*intervention*each poorer IC subdomains) were added to GLMM models. Significant improvements in MoCA scores were shown for participants with poorer baseline cognition (coefficient= 1.138, 95% CI: 0.080 ~ 2.195) and vitality domains (coefficient= 1.651, 95% CI: 0.541 ~ 2.760). The poor vitality domain also had a significant modulating effect on the reduction of CHS frailty score after the 6- and 12-month intervention period (6 months: coefficient= -0.311, 95% CI: -0.554 ~ -0.068; 12 months: coefficient= -0.257, 95% CI: -0.513 ~ -0.001).
CONCLUSION AND IMPLICATIONS: A multidomain intervention in community-dwelling older adults improves cognitive decline and physical frailty, with its effectiveness influenced by baseline IC, highlighting the importance of personalized strategies for healthy aging.
CITATION:
C.-K. Liang ; W.-J. Lee ; M.-Y. Chou ; A.-C. Hwang ; C.-S. Lin ; L.-N. Peng ; F.-Y. Hsiao ; C.-H. Loh ; L.-K. Chen ; (2024): Roles of Baseline Intrinsic Capacity and its Subdomains on the Overall Efficacy of Multidomain Intervention in Promoting Healthy Aging among Community-Dwelling Older Adults: Analysis from a Nationwide Cluster-Randomized Controlled Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.20
A PHASE 1 SINGLE-ASCENDING-DOSE TRIAL IN HEALTHY VOLUNTEERS TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND IMMUNOGENICITY OF INTRAVENOUS PNT001, A NOVEL MID-DOMAIN TAU ANTIBODY TARGETING CIS-PT231 TAU
W. Luca, K. Foster, K. McClure, M.K. Ahlijanian, M. Jefson
J Prev Alz Dis 2024;2(11):366-374
Show summaryHide summaryBACKGROUND: PNT001 is a humanized full-length IgG4 S228P monoclonal antibody that binds the cis conformation of the phosphorylated Thr231-Pro232 motif in human full-length (2N4R) tau (cis-pT231 tau) with high selectivity and affinity. It binds selectively to cis-pT231 tau in human tauopathy brain sections, inhibits aggregation of tau, and has shown efficacy in preclinical models of tauopathy. Good Laboratory Practice six-month toxicology studies in cynomolgous monkeys have shown no test article-related findings.
OBJECTIVES: To evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of single escalating intravenous doses of PNT001 in healthy volunteers.
DESIGN: Phase 1, randomized, double-blind, and placebo-controlled 16-week study.
SETTING: Subjects were recruited across three clinical research sites in the United States.
PARTICIPANTS: Fifty healthy volunteer subjects enrolled, with 49 receiving the double-blind study drug.
INTERVENTION: Six cohorts were administered single escalating doses of PNT001 (33, 100, 300, 900, 2,700, and 4,000 mg). The subjects were randomized 6:2 (PNT001:placebo).
MEASUREMENTS: Safety was evaluated by the occurrence of adverse events, electrocardiography, physical examinations, neurological examinations, vital signs, and suicidality. Pharmacokinetics and biomarkers were assessed via serum and cerebrospinal fluid sample analyses.
RESULTS: Dose continuation after review of sentinel group data and dose escalation after completion of full cohort data were determined by an external, independent safety board. There were no study pauses or safety concerns identified by the safety board. A total of 49 subjects received the study drugs, with 36 receiving PNT001 and 13 receiving placebo. There were three related non-serious adverse events, each Grade 1, which occurred at the lowest doses and resolved without sequelae. No maximum tolerated dose was identified, and no premature discontinuations, dose reductions, or interruptions due to treatment-related adverse events occurred. One unrelated serious adverse event occurred in a placebo subject with an undisclosed medical condition. No other safety findings were identified. Doses of 900–4,000 mg produced concentrations in the cerebrospinal fluid exceeding the binding affinity constant of PNT001 for cis-pT231 tau (45 ng/mL), indicating that concentrations sufficient for target engagement can be obtained in the cerebrospinal fluid within the tested dose range. The serum pharmacokinetic profile was as expected for a monoclonal antibody. The terminal half-lives ranged from 23.8–33.8 days, and the cerebrospinal fluid exposures were approximately 0.1% of the plasma concentration and dose-proportional. Of the 36 subjects receiving PNT001, one post-baseline positive anti-drug antibody result was observed at Day 112 in a subject who received PNT001 (300 mg).
CONCLUSIONS: Single doses of PNT001 were safe and well-tolerated at all dose levels studied, including those doses expected to produce therapeutic benefit. These results support multiple ascending dose trials in patients with neurodegenerative tauopathies for this novel mid-domain tau antibody.
CITATION:
W. Luca ; K. Foster ; K. McClure ; M.K. Ahlijanian ; M. Jefson ; (2024): A Phase 1 Single-Ascending-Dose Trial in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics, and Immunogenicity of Intravenous PNT001, a Novel Mid-domain Tau Antibody Targeting cis-pT231 Tau. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.25
VORTIOXETINE TREATMENT FOR DEPRESSION IN PATIENTS WITH PRODROMAL VS MILD ALZHEIMER’S DISEASE: A SIXMONTH, OPEN-LABEL, OBSERVATIONAL STUDY
A. Padovani, S. Caratozzolo, A. Benussi, A. Galli, L. Rozzini, M. Cosseddu, R. Turrone, A. Pilotto
J Prev Alz Dis 2024;2(11):375-381
Show summaryHide summaryBACKGROUND: Depressive symptoms are common in Alzheimer disease (AD) from the prodromal stage. The benefits of antidepressants have been investigated in patients with AD dementia with mixed results.
OBJECTIVES: This study aimed to compare the efficacy of vortioxetine in prodromal and mild-to-moderate AD patients with depression, and to assess the comparative effect on secondary measures, including behavioral disturbances, cognitive function, and activities of daily living.
PARTICIPANTS: All subjects with AD at a single-center dementia center underwent a standard evaluation with mini-mental state examination (MMSE), basic and instrumental activities of daily living (BADL and IADL), geriatric depression scale (GDS), neuropsychiatric inventory (NPI), and clinical evaluation every six months.
MEASUREMENTS: The study specifically assessed patients on vortioxetine with available six-month follow-up data. The changes in GDS, NPI, MMSE, BADL/IADL at six months in the entire AD population and mild-to-moderate AD vs prodromal population were analyzed using repeated measure multivariate analyses. Linear regression analyses were implemented to evaluate baseline demographics and clinical characteristics associated with depressive and cognitive improvements at six months.
RESULTS: Out of 680 AD patients, 115 were treated with vortioxetine, and 89 with six-month follow-up data were included in the analyses. A significant improvement at follow-up was observed for GDS, NPI total and sub score items (mood, anxiety, apathy, sleep disturbances, eating abnormalities). Both mild-to-moderate and prodromal AD showed a positive GDS response, whereas mild-to-moderate AD showed a better improvement on total NPI and apathy/nighttime behaviors subitems compared to prodromal AD. Higher baseline GDS score was the only variable associated with higher responses in linear regression analyses. MMSE showed a significant improvement at six months in the entire cohort, with a greater effect in prodromal vs mild-to-moderate AD. Cognitive improvement (i.e., MMSE changes) was associated with cognitive status at baseline but independent of the antidepressant/behavioral changes (i.e., GDS/NPI).
CONCLUSIONS: Our results suggest that vortioxetine is highly tolerable and clinically effective in both prodromal and mild-to-moderate AD with depression. Patients with mild-to-moderate AD benefited more from a wide range of behavioral disturbances. The study also showed significant improvement in global cognitive measures, especially in prodromal AD subjects. Further studies are needed to investigate the independent beneficial effect of vortioxetine on depression and cognition in AD.
CITATION:
A. Padovani ; S. Caratozzolo ; A. Benussi ; A. Galli ; L. Rozzini ; M. Cosseddu ; R. Turrone ; A. Pilotto ; (2023): Vortioxetine Treatment for Depression in Patients with Prodromal vs Mild Alzheimer’s Disease: A Six-Month, Open-Label, Observational Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.132
A CHOLECYSTOKININ ANALOGUE AMELIORATES COGNITIVE DEFICITS AND REGULATES MITOCHONDRIAL DYNAMICS VIA THE AMPK/DRP1 PATHWAY IN APP/PS1 MICE
L. Hao, M. Shi, J. Ma, S. Shao, Y. Yuan, J. Liu, Z. Yu, Z. Zhang, C. Hölscher, Z. Zhang
J Prev Alz Dis 2024;2(11):382-401
Show summaryHide summaryBACKGROUND: There are no drugs on the market that can reverse or slow Alzheimer’s disease (AD) progression. A protease-resistant Cholecystokinin (CCK) analogue used in this study is based on the basic structure of CCK, which further increases the stability of the peptide fragment and prolongs its half-life in vivo. We observed a neuroprotective effect of CCK-8L in APPswe/PS1dE9 (APP/PS1) AD mice. However, its corresponding mechanisms still need to be elucidated.
OBJECTIVE: This study examined CCK-8L’s neuroprotective effects in enhancing cognitive impairment by regulating mitochondrial dynamics through AMPK/Drp1 pathway in the APP/PS1 AD mice.
METHODS: Behavioural tests are applied to assess competence in cognitive functions. Transmission electron microscopy (TEM) was performed to observe the ultrastructure of mitochondria of hippocampal neurons, Immunofluorescent staining was employed to assay for Aβ1-42, APP, Adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) and dynamin-related protein1 (Drp1). CRISPR/Cas9 was utilized for targeted knockout of the CCKB receptor (CCKBR) in the mouse APP/PS1 hippocampal CA1 region. A model of lentiviral vector-mediated overexpression of APP in N2a cells was constructed.
RESULTS: In vivo, experiments revealed that CCK analogue and liraglutide significantly alleviated cognitive deficits in APP/PS1 mice, reduced Aβ1-42 expression, and ameliorated l damage, which is associated with CCKBR activation in the hippocampal CA1 region of mice. In vitro tests showed that CCK inhibited mitochondrial fission and promoted fusion through AMPK/Drp1 pathway.
CONCLUSIONS: CCK analogue ameliorates cognitive deficits and regulates mitochondrial dynamics by activating the CCKB receptor and the AMPK/Drp1 pathway in AD mice.
CITATION:
L. Hao ; M. Shi ; J. Ma ; S. Shao ; Y. Yuan ; J. Liu ; Z. Yu ; Z. Zhang ; C. Hölscher ; Z. Zhang (2024): A Cholecystokinin Analogue Ameliorates Cognitive Deficits and Regulates Mitochondrial Dynamics via the AMPK/Drp1 Pathway in APP/PS1 Mice. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.6
COST-EFFECTIVENESS OF PREVENTION FOR PEOPLE AT RISK FOR DEMENTIA: A SCOPING REVIEW AND QUALITATIVE SYNTHESIS
A. Braun, M. Höfler, S. Auer
J Prev Alz Dis 2024;2(11):402-413
Show summaryHide summaryDementia is from an economic perspective a main challenge for economies worldwide because of increasing costs. Since there is no cure in sight, prevention seems the most promising approach for reducing health care cost due to Dementia. On the contrary, approximately 40% of dementias is attributable to modifiable risk factors and first studies showed that multidomain interventions may be effective for preventing dementia. Considering the increasing economic burden, for many health administrations worldwide, cost-effectiveness plays a mayor role. This scoping review wants to bring evidence to the question if prevention for people at risk may be cost-effective. Therefore, the four databases Medline (via Pubmed), CINHAL (via EBSCO), Business Source Complete (via EBSCO), and the Health Economic Evaluation database (HEED) were used to conduct a scoping review using PICO and a systematic search string. 3,629 studies were identified and seven met all inclusion criteria. The included studies showed clear cost-effectiveness for most multidomain interventions. The gained QALYs at mean were 0.08 (SD=0.08) and the intervention average costs 472.20 EUR per Person (SD=74.06 EUR). The Incremental Cost-Effectiveness Ratios varied between –80,427.97 and 104,189.82 EUR per QALY. The three core results are (i) prevention programs focusing on people at risk may be cost-effective and cost-efficient, (ii) multimodal prevention reveal cost saving potential, when the people at risk are defined well, (iii prevention in middle-aged cohorts may be also cost-effective if life-style related risk factors are addressed.
CITATION:
A. Braun ; M. Höfler ; S. Auer ; (2024): Cost-Effectiveness of Prevention for People at Risk for Dementia: A Scoping Review and Qualitative Synthesis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.12
CLINICAL CORRELATES OF THE PET-BASED BRAAK STAGING FRAMEWORK IN ALZHEIMER’S DISEASE
A.C. Macedo, D.F.P.A. Durço, C. Tissot, J. Therriault, A.O. Vilela de Faria, É. Aumont, S. Servaes, N. Rahmouni, J. Fernandez-Arias, Y.-T. Wang, F.Z. Lussier, A. Bieger, E.R. Zimmer, T.A. Pascoal, S. Gauthier, P. Rosa-Neto
J Prev Alz Dis 2024;2(11):414-421
Show summaryHide summaryIn vivo Alzheimer’s disease diagnosis and staging is traditionally based on clinical features. However, the agreement between clinical and pathological Alzheimer’s disease diagnosis, whose diagnosis assessment includes amyloid and Braak histopathological tau staging, is not completely convergent. The development of positron emission tomography (PET) tracers targeting neurofibrillary tangles offers prospects for advancing the staging of Alzheimer’s disease from both biological and clinical perspectives. Recent advances in radiochemistry made it possible to apply the postmortem Braak staging framework to tau-PET images obtained in vivo. Here, our aim is to provide a narrative review of the current literature on the relationship between Alzheimer’s disease clinical features and the PET-based Braak staging framework. Overall, the available studies support the stepwise increase in disease severity following the advance of PET-based Braak stages, with later stages being associated with worse cognitive and clinical symptoms. In line with this, there is a trend for unimpaired cognition, mild cognitive impairment, and Alzheimer’s disease dementia to be compatible with early, intermediate, and late patterns of tau deposition based on PET-based Braak stages. Moreover, neuropsychiatric symptom severity seems to be linked to the extent of tau-PET signal across Braak areas. In sum, this framework seems to correspond well with the clinical progression of Alzheimer’s disease, which is an indication of its potential utility in research and clinical practice, especially for detecting preclinical tau levels in individuals without symptoms. However, further research is needed to improve the generalizability of these findings and to better understand the applications of this staging framework.
CITATION:
A.C. Macedo ; D.F.P.A. Durço ; C. Tissot ; J. Therriault ; A.O. Vilela de Faria ; É. Aumont ; S. Servaes ; N. Rahmouni ; J. Fernandez-Arias ; Y.-T. Wang ; F.Z. Lussier ; A. Bieger ; E.R. Zimmer ; T.A. Pascoal ; S. Gauthier ; P. Rosa-Neto ; (2024): Clinical Correlates of the PET-based Braak Staging Framework in Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.15
CYTOMEGALOVIRUS INFECTION AND ALZHEIMER’S DISEASE: A META-ANALYSIS
Q. Ji, W. Lian, Y. Meng, W. Liu, M. Zhuang, N. Zheng, I.K. Karlsson, Y. Zhan
J Prev Alz Dis 2024;2(11):422-427
Show summaryHide summaryBackground: Evidence on the association of cytomegalovirus (CMV) infection with Alzheimer’s disease (AD) is scarce and the results are inconsistent.
OBJECTIVE: To investigate the association of CMV infection with the risk of AD.
METHODS: Observational studies on the relationship between CMV infection and AD were identified from PubMed, Embase, Web of Science, and the Cochrane Library until September 30, 2022. The quality of included studies was assessed using the Newcastle-Ottawa Scale. Random-effect meta-analysis was performed using a generic inverse-variance method, followed by sensitivity analyses and subgroup analyses based on study designs, regions, adjustments, and population types.
RESULTS: Our search yielded 870 articles, of which 200 were duplicates and 663 did not meet the inclusion criteria, and finally yielded seven studies with 6,772 participants. No strong evidence was observed in the summary analysis for the association of CMV infection and risk of AD (odds ratio [OR] = 1.33; 95% confidence interval [CI]: 0.88, 2.03, I2 =69.9%). However, subgroup analysis showed that an increased risk of AD was detected in East Asians (OR = 2.39; 95% CI: 1.63, 3.50, I2 = 0.00%), cohort studies (OR = 1.99; 95% CI: 1.35, 2.94, I2 = 28.20%), and studies with confounder adjustment (OR = 2.05; 95% CI: 1.52, 2.77, I2 = 0.00%).
CONCLUSIONS: This meta-analysis provides evidence to support the heterogeneity of the associations between CMV infection and AD. Future studies with larger sample sizes and multi-ethnic populations are necessary.
CITATION:
Q. Ji ; W. Lian ; Y. Meng ; W. Liu ; M. Zhuang ; N. Zheng ; I.K. Karlsson ; Y. Zhan ; (2023): Cytomegalovirus Infection and Alzheimer’s Disease: A Meta-Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.126
NANOLITHIUM, A NEW TREATMENT APPROACH TO ALZHEIMER’S DISEASE: A REVIEW OF EXISTING EVIDENCE AND CLINICAL PERSPECTIVES
S. Guilliot, E.N. Wilson, J. Touchon, M.E. Soto
J Prev Alz Dis 2024;2(11):428-434
Show summaryHide summaryLithium has been approved and used for several decades in the treatment of psychiatric disorders, and its potential effect in neurodegenerative diseases has been subject to increasing research interest in recent years. Nanolithium is a new experimental product using a novel drug-delivery technology (Aonys®), which optimizes its bioavailability while reducing its toxicity profile. Therapeutic doses of lithium used in Nanolithium are more than 50 times lower than the minimal dose of classical lithium salts. In this review we report data from non-clinical pharmacology studies supporting Nanolithium efficacy and the mechanism of action in Alzheimer’s disease. GSK-3β inhibition is thought to be central to Nanolithium’s mechanism of action, triggering a reduction of the production of toxic amyloid plaques and decrease in tau hyperphosphorylation, which could potentially benefit both neuropsychiatric symptoms and cognitive decline. We then summarize outcomes from non-clinical proof-of-concept studies. These data supported the initiation of a currently ongoing phase II proof-of-concept study to evaluate the safety and efficacy of Nanolithium in patients with mild-to-severe Alzheimer’s disease. We highlight key aspects of the study design. We finish this review with a discussion on the potential place of Nanolithium in the current and future Alzheimer’s disease treatment landscape.
CITATION:
S. Guilliot ; E.N. Wilson ; J. Touchon ; M.E. Soto (2024): Nanolithium, a New Treatment Approach to Alzheimer’s Disease: A Review of Existing Evidence and Clinical Perspectives. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.26
PERSONALIZED COMPUTATIONAL CAUSAL MODELING OF THE ALZHEIMER DISEASE BIOMARKER CASCADE
J.R. Petrella, J. Jiang, K. Sreeram, S. Dalziel, P.M. Doraiswamy, W. Hao, for the Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2024;2(11):435-444
Show summaryHide summaryBACKGROUND: Mathematical models of complex diseases, such as Alzheimer’s disease, have the potential to play a significant role in personalized medicine. Specifically, models can be personalized by fitting parameters with individual data for the purpose of discovering primary underlying disease drivers, predicting natural history, and assessing the effects of theoretical interventions. Previous work in causal/mechanistic modeling of Alzheimer’s Disease progression has modeled the disease at the cellular level and on a short time scale, such as minutes to hours. No previous studies have addressed mechanistic modeling on a personalized level using clinically validated biomarkers in individual subjects.
OBJECTIVES: This study aimed to investigate the feasibility of personalizing a causal model of Alzheimer’s Disease progression using longitudinal biomarker data.
DESIGN/SETTING/PARTICIPANTS/MEASUREMENTS: We chose the Alzheimer Disease Biomarker Cascade model, a widely-referenced hypothetical model of Alzheimer’s Disease based on the amyloid cascade hypothesis, which we had previously implemented mathematically as a mechanistic model. We used available longitudinal demographic and serial biomarker data in over 800 subjects across the cognitive spectrum from the Alzheimer’s Disease Neuroimaging Initiative. The data included participants that were cognitively normal, had mild cognitive impairment, or were diagnosed with dementia (probable Alzheimer’s Disease). The model consisted of a sparse system of differential equations involving four measurable biomarkers based on cerebrospinal fluid proteins, imaging, and cognitive testing data.
RESULTS: Personalization of the Alzheimer Disease Biomarker Cascade model with individual serial biomarker data yielded fourteen personalized parameters in each subject reflecting physiologically meaningful characteristics. These included growth rates, latency values, and carrying capacities of the various biomarkers, most of which demonstrated significant differences across clinical diagnostic groups. The model fits to training data across the entire cohort had a root mean squared error (RMSE) of 0.09 (SD 0.081) on a variable scale between zero and one, and were robust, with over 90% of subjects showing an RMSE of < 0.2. Similarly, in a subset of subjects with data on all four biomarkers in at least one test set, performance was high on the test sets, with a mean RMSE of 0.15 (SD 0.117), with 80% of subjects demonstrating an RMSE < 0.2 in the estimation of future biomarker points. Cluster analysis of parameters revealed two distinct endophenotypic groups, with distinct biomarker profiles and disease trajectories.
CONCLUSION: Results support the feasibility of personalizing mechanistic models based on individual biomarker trajectories and suggest that this approach may be useful for reclassifying subjects on the Alzheimer’s clinical spectrum. This computational modeling approach is not limited to the Alzheimer Disease Biomarker Cascade hypothesis, and can be applied to any mechanistic hypothesis of disease progression in the Alzheimer’s field that can be monitored with biomarkers. Thus, it offers a computational platform to compare and validate various disease hypotheses, personalize individual biomarker trajectories and predict individual response to theoretical prevention and therapeutic intervention strategies.
CITATION:
J.R. Petrella ; J. Jiang ; K. Sreeram ; S. Dalziel ; P.M. Doraiswamy ; W. Hao ; for the Alzheimer’s Disease Neuroimaging Initiative (2023): Personalized Computational Causal Modeling of the Alzheimer Disease Biomarker Cascade. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.134
FRUIT INTAKE AND ALZHEIMER’S DISEASE: RESULTS FROM MENDELIAN RANDOMIZATION
W.-Z. Liao, X.-F. Zhu, Q. Xin, Y.-T. Mo, L.-L. Wang, X.-P. He, X.-G. Guo
J Prev Alz Dis 2024;2(11):445-452
Show summaryHide summaryAlzheimer’s disease (AD) is the leading cause of dementia in old age, recognized as a global health priority. To explore causal effects of fresh fruit intake and dried fruit intake on AD liability, this study utilized GWAS from the UK Biobank and FinnGen to conduct Mendelian randomization (MR) analysis, and used inverse variance weighted (IVW), MR-Egger, and weighted median approaches for MR estimates, and visual inspections judged result stability. Results suggested little evidence of a potential causal relationship between fresh fruit intake and AD (OR=0.97, 95%CI=0.50-1.91, P=0.939), while significant, robust causality was indicated between dried fruit intake and AD (OR=4.09, 95%CI=2.07-8.10, P<0.001). Stability evaluations showed no heterogeneity or pleiotropy affecting interpretability and credibility of primary analyses. In conclusion, we strengthened evidence for positive causality from dried fruit intake to AD liability, with causality from fresh fruit intake on AD risk was not demonstrated.
CITATION:
W.-Z. Liao ; X.-F. Zhu ; Q. Xin ; Y.-T. Mo ; L.-L. Wang ; X.-P. He ; X.-G. Guo (2024): Fruit Intake and Alzheimer’s Disease: Results from Mendelian Randomization. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.31
CARDIOVASCULAR RISK SCALES ASSOCIATION WITH CEREBROSPINAL FLUID ALZHEIMER’S DISEASE BIOMARKERS IN CARDIOVASCULAR LOW CARDIOVASCULAR RISK REGIONS
G. García-Lluch, J. Pardo, L. Moreno, C. Peña-Bautista, M. Baquero, C. Cháfer-Pericás
J Prev Alz Dis 2024;2(11):453-462
Show summaryHide summaryBACKGROUND: Cardiovascular risk factors are associated with Alzheimer’s Disease (AD) development. However, few studies compare the overall cardiovascular risk with AD biomarkers, and when done, they are mainly performed in moderate cardiovascular risk regions.
OBJECTIVES: To determine whether cardiovascular risk in older adults is associated with pathological cerebrospinal fluid (CSF) biomarkers of AD in a low cardiovascular risk population.
DESIGN: This is a cross-sectional study performed between 2017 and 2020.
PARTICIPANTS: The present work included patients between 50 and 75 years old who were negative for CSF AD biomarkers and had minimum cognitive alterations (controls) and patients with positive CSF AD biomarkers and in early stages of AD (cases).
MEASUREMENTS: CSF biomarkers included total tau, phosphorylated tau 181 and amyloid ß42 (Aß42). Analytical variables were obtained. ERICE, SCORE2 and Framingham scales were used to calculate the overall patient’s cardiovascular risk. The Aß42/Aß40 ratio and neurofilaments were explored when available.
RESULTS: Two hundred and thirty-three patients were included. Nearly 76% of the sample had AD. AD patients had higher cardiovascular risk than controls (p-value < 0.05). ERICE and SCORE2 were associated with AD presence. Framingham was not. A correlation between elevated cardiovascular risk and higher total tau and NfL levels was observed when adjusted by age.
CONCLUSION: Cardiovascular risk assessment may be helpful in neurodegenerative disorders detection, as it is associated with CSF total tau and NfL. ERICE and SCORE2 may be useful scales in low cardiovascular risk regions to improve cardiovascular control and prevent neurodegenerative pathologies.
CITATION:
G. García-Lluch ; J. Pardo ; L. Moreno ; C. Peña-Bautista ; M. Baquero ; C. Cháfer-Pericás (2024): Cardiovascular Risk Scales Association with Cerebrospinal Fluid Alzheimer’s Disease Biomarkers in Cardiovascular Low Cardiovascular Risk Regions. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.16
THE MAPP ROOM MEMORY TEST: EXAMINING CONTEXTUAL MEMORY USING A NOVEL COMPUTERIZED TEST IN COGNITIVELYUNIMPAIRED INDIVIDUALS WITH AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE
A. Giudicessi, P.A. Aduen, J.T. Fox-Fuller, J.E. Martinez, L.A. Gonzalez, C. Vila-Castelar, A. Baena, C. Pluim McDowell, A. Cronin-Golomb, F. Lopera, Y.T. Quiroz
J Prev Alz Dis 2024;2(11):463-468
Show summaryHide summaryContextual memory, the ability to remember spatial or temporal features related to an event, is affected in Alzheimer’s disease (AD). There is a shortfall of tests that measure contextual memory. To evaluate visuospatial contextual memory, we developed a computerized cognitive test, the MAPP Room Memory Test, which requires participants to identify in which visual scene target items were previously presented. We hypothesized that cognitively-unimpaired carriers of an autosomal dominant AD mutation (Presenilin-1 E280A, n=15) would perform more poorly on this test than non-carrier family members (n=31). Compared to non-carriers, the carriers had significantly worse delayed room recognition. The results indicate that the MAPP Room Memory Test may be sensitive to subtle cognitive changes associated with risk of AD. Future studies with larger samples using the MAPP Room Memory Test and biomarkers are needed to examine whether this test may also be sensitive to the earliest pathological changes in preclinical AD.
CITATION:
A. Giudicessi ; P.A. Aduen ; J.T. Fox-Fuller ; J.E. Martinez ; L.A. Gonzalez ; C. Vila-Castelar ; A. Baena ; C. Pluim McDowell ; A. Cronin-Golomb ; F. Lopera ; Y.T. Quiroz ; (2024): The MAPP Room Memory Test: Examining Contextual Memory Using a Novel Computerized Test in Cognitively-Unimpaired Individuals with Autosomal Dominant Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.7
BEYOND VISION: A VIEW FROM EYE TO ALZHEIMER’S DISEASE AND DEMENTIA
C. Zheng, R. Zeng, G. Wu, Y. Hu, H. Yu
J Prev Alz Dis 2024;2(11):469-483
Show summaryHide summaryWith the aging of the global population, the health care burden of Alzheimer’s disease (AD) and dementia is considered to increase dramatically in the coming decades. Given the insufficiency of effective interventions for AD and dementia, clinical research on identifying potentially modifiable risk factors and early diagnostic biomarkers becomes a public health priority. Currently, extracerebral manifestations with a large proportion of ocular involvement are usually recognized to precede the symptoms of AD and dementia. Growing epidemiologic evidence also suggests that eye disorders, such as cataracts, age-related macular degeneration, glaucoma, diabetic retinopathy, and so on, are closely associated with and even have a higher incidence of AD and dementia. The eye, as an extension of the central nervous system, therefore has the potential to provide a feasible approach to detecting structural and functional abnormalities of the brain. Numerous new imaging modalities are developed and give novel insights into the detection of several neurodegenerative, vascular, neuropathological, and other ocular abnormalities of AD and dementia in scientific research and clinical application. This review provides an overview of the epidemiologic associations between eye disorders and AD or dementia and summarizes the recent advances in ocular examinations and techniques employed for the detection of AD and dementia. With more brain-and-eye interconnections being identified, the eye is becoming a noninvasive and easily accessible window for the early diagnosis and prevention of AD and dementia.
CITATION:
C. Zheng ; R. Zeng ; G. Wu ; Y. Hu ; H. Yu (2023): Beyond Vision: A View from Eye to Alzheimer’s Disease and Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.118
HIGHER COGNITIVE RESERVE IS BENEFICIAL FOR COGNITIVE PERFORMANCE VIA VARIOUS LOCUS COERULEUS FUNCTIONAL PATHWAYS IN THE PRE-DEMENTIA STAGE OF ALZHEIMER’S DISEASE
L. Gong, K. Chen, H. Zhang, S. Zhang, W. Luo, W. Zhou, B. Zhang, R. Xu, C. Xi, for the Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2024;2(11):484-494
Show summaryHide summaryBACKGROUND: Cognitive reserve (CR) shows protective effects on cognitive function in older adult and in Alzheimer’s disease (AD). However, the brain mechanisms underlying the CR effect on the non-dementia AD spectrum (subjective cognitive decline (SCD) and mild cognitive impairment (MCI)) are unknown. The aim of this study was to investigate the potential moderate effect of CR on brain functional networks associated with cognitive performance.
METHODS: We selected 200 participants, including 48 cognitively normal (CN) and 56 SCD, and 96 patients with MCI from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Seed-based locus coeruleus functional connectivity (LC FC) was conducted to detect early brain functional changes in the non-dementia AD spectrum. CR was assessed via years of education and intelligence (IQ). The ANDI composite executive function scores (ADNI-EF) and ADNI composite memory scores (ANDI-MEM) at baseline and 24-month follow-up were used to assess cognitive performance.
RESULTS: Compared to the CN group, the SCD group showed abnormal LC FC with the executive control network (dorsolateral prefrontal cortex, DLPFC), salience network, sensorimotor network, reward network, and hippocampus, while these alterations were inverted at the MCI stage. The LC-hippocampus FC was correlated with ADNI-MEM at baseline and follow-up, and these relationships were moderated by education. The LC-DLPFC FC was correlated with ADNI-EF at baseline, and this association was moderated by IQ.
CONCLUSION: Our results manifested that higher levels of CR would confer protective effects on SCD and MCI. Furthermore, IQ and education could moderate the relationship between LC FC and cognition through different pathways.
CITATION:
L. Gong ; K. Chen ; H. Zhang ; S. Zhang ; W. Luo ; W. Zhou ; B. Zhang ; R. Xu ; C. Xi (2023): Higher Cognitive Reserve Is Beneficial for Cognitive Performance Via Various Locus Coeruleus Functional Pathways in the Pre-Dementia Stage of Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.127
INTEGRATED BIOINFORMATIC ANALYSIS AND VALIDATION IDENTIFIES IMMUNE MICROENVIRONMENT-RELATED POTENTIAL BIOMARKERS IN ALZHEIMER’S DISEASE
F. Yang, N. Zhang, G.-Y. Ou, S.-W. Xu
J Prev Alz Dis 2024;2(11):495-506
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases, accompanied by cognitive and memory impairment, accounting for about 60% - 80% of dementia types. The pathogenesis of AD has not been clarified, and there is no effective therapy to prevent or treat AD. In this study, we aimed to identify the potential biomarkers involved in the brain immune microenvironment in AD.
METHODS: AD datasets from GEO database were obtained to identify the differentially expressed disease-related genes (DEDRGs) in AD through weighted gene co-expression network analysis (WGCNA) and differential expression analysis. Functional Enrichment analysis was performed to explore the potential biological function of DEDRGs. The hub DEDRGs were identified through the protein-protein interaction (PPI) network. Furthermore, the CIBERSORT algorithm was employed to bulk gene expression profiles of AD to depict the immune microenvironment characteristics in AD. Pearson’s correlation analysis was utilized to depict the correlation between each of immune cells and hub DEDRGs.
RESULTS: A total of 27 DEDRGs were identified through WGCNA and differential expression analysis. Functional enrichment analysis of 27 DEDRGs indicated that chemokine signaling pathway was the most significantly enriched KEGG pathway, response to biotic stimulus was the most significantly enriched GO term, and most of DEDRGs were enriched into urinary system cancer in DO analysis. 6 hub DEDRGs, ANGPT1, CCL2, CD44, CXCR4, GJA1 and VCAM1, were screened through PPI network and all of them were up-regulated in AD. Immune infiltration analysis revealed that there were higher infiltration levels of T cells CD4 memory activated, T cells gamma delta, NK cells resting and macrophages M0, and lower infiltration level of NK cell activated in AD, and macrophages M2 owned the highest positively association with VCAM1 and CXCR4, but VCAM1 was statistically and negatively correlated to T cells CD8.
CONCLUSION: Our study identified 6 hub DEDRGs, ANGPT1, CCL2, CD44, CXCR4, GJA1 and VCAM1, were statistically associated with immune infiltrating cells, and were significantly related to the pathological development of AD, which may provide a theoretical basis for developing potential biomarkers and implementing effective therapies against AD.
CITATION:
F. Yang ; N. Zhang ; G.-Y. Ou ; S.-W. Xu ; (2024): Integrated Bioinformatic Analysis and Validation Identifies Immune Microenvironment-Related Potential Biomarkers in Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.5
THE IMPACT OF TESTOSTERONE ON ALZHEIMER’S DISEASE ARE MEDIATED BY LIPID METABOLISM AND OBESITY: A MENDELIAN RANDOMIZATION STUDY
L. Zhang, F. Yang, J. Ma, Y. Hu, M. Li, C. Wang, X. Chang, L. Yang
J Prev Alz Dis 2024;2(11):507-513
Show summaryHide summaryBACKGROUND: To investigate the causal relationship between testosterone (BT) levels and Alzheimer’s disease (AD) risk and to quantify the role of obesity and lipid metabolism as potential mediators.
METHODS: We used a two-sample, two-step MR to determine:1) the causal effect of BT levels on AD; 2) the causal effect of two lipid metabolites, obesity and LDLc on AD; and 3) the mediating effects of these metabolites. Pooled data for BT levels and lipid metabolism were obtained from the UK Biobank. AD data were obtained from the Alzheimer’s Disease Project International Genomics Consortium, FinnGen Consortium, and UK Biobank study. Effect estimates from external genome-wide association study (GWAS) pooled statistics were obtained using inverse variance-weighted (IVW) MR analysis.
RESULTS: Higher levels of BT were associated with a reduced risk of AD (odds ratio [OR] 0.9992, 95% CI 0.9985-0.9998, P = 0.019), and there was a negative correlation with LDLc (OR 0.9208, 95% CI 0.8569-0.9895, P = 0.024) and obesity class 2 (OC2) (OR 0.7445, 95% CI 0.5873-0.9437, P = 0.014). Conversely, there was a positive correlation between LDLc (OR 1.0014, 95% CI 1.0000-1.0029, P = 0.043) and OC2 (OR 1.0005, 95% CI 1.0001-1.0009, P = 0.003) and AD. Mediation analysis showed that the indirect effect of BT levels on AD was achieved through LDLc and OC2, which accounted for 17% and 17% of the total effect, respectively.
CONCLUSION: Our study identified a causal role of BT levels in LDLc and OC2. BT levels may affect AD through LDLc and OC2 metabolic processes.
CITATION:
L. Zhang ; F. Yang ; J. Ma ; Y. Hu ; M. Li ; C. Wang ; X. Chang ; L. Yang ; (2023): The Impact of Testosterone on Alzheimer’s Disease Are Mediated by Lipid Metabolism and Obesity: A Mendelian Randomization Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.116
UNSUPERVISED ONLINE PAIRED ASSOCIATES LEARNING TASK FROM THE CAMBRIDGE NEUROPSYCHOLOGICAL TEST AUTOMATED BATTERY (CANTAB®) IN THE BRAIN HEALTH REGISTRY
M.T. Ashford, A. Aaronson, W. Kwang, J. Eichenbaum, S. Gummadi, C. Jin, N. Cashdollar, E. Thorp, E. Wragg, K.H. Zavitz, F. Cormack, T. Banh, J.M. Neuhaus, A. Ulbricht, M.R. Camacho, J. Fockler, D. Flenniken, D. Truran, R.S. Mackin, M.W. Weiner, R.L. Nosheny
J Prev Alz Dis 2024;2(11):514-524
Show summaryHide summaryBACKGROUND: Unsupervised online cognitive assessments have demonstrated promise as an efficient and scalable approach for evaluating cognition in aging, and Alzheimer’s disease and related dementias.
OBJECTIVES: The aim of this study was to evaluate the feasibility, usability, and construct validity of the Paired Associates Learning task from the Cambridge Neuropsychological Test Automated Battery® in adults enrolled in the Brain Health Registry.
DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: The Paired Associates Learning task was administered to Brain Health Registry participants in a remote, unsupervised, online setting. In this cross-sectional analysis, we 1) evaluated construct validity by analyzing associations between Paired Associates Learning performance and additional participant registry data, including demographics, self- and study partner-reported subjective cognitive change (Everyday Cognition scale), self-reported memory concern, and depressive symptom severity (Patient Health Questionnaire-9) using multivariable linear regression models; 2) determined the predictive value of Paired Associates Learning and other registry variables for identifying participants who self-report Mild Cognitive Impairment by employing multivariable binomial logistic regressions and calculating the area under the receiver operator curve; 3) investigated feasibility by looking at task completion rates and statistically comparing characteristics of task completers and non-completers; and 4) evaluated usability in terms of participant requests for support from BHR related to the assessment.
RESULTS: In terms of construct validity, in participants who took the Paired Associates Learning for the first time (N=14,528), worse performance was associated with being older, being male, lower educational attainment, higher levels of self- and study partner-reported decline, more self-reported memory concerns, greater depressive symptom severity, and self-report of Mild Cognitive Impairment. Paired Associates Learning performance and Brain Health Registry variables together identified those with self-reported Mild Cognitive Impairment with moderate accuracy (areas under the curve: 0.66-0.68). In terms of feasibility, in a sub-sample of 29,176 participants who had the opportunity to complete Paired Associates Learning for the first time in the registry, 14,417 started the task. 11,647 (80.9% of those who started) completed the task. Compared to those who did not complete the task at their first opportunity, those who completed were older, had more years of education, more likely to self-identify as White, less likely to self-identify as Latino, less likely to have a subjective memory concern, and more likely to report a family history of Alzheimer’s disease. In terms of usability, out of 8,395 received requests for support from BHR staff via email, 4.4% (n=374) were related to PAL. Of those, 82% were related to technical difficulties.
CONCLUSIONS: Our findings support moderate feasibility, good usability, and construct validity of cross-sectional Paired Associates Learning in an unsupervised online registry, but also highlight the need to make the assessment more inclusive and accessible to individuals from ethnoculturally and socioeconomically diverse communities. A future, improved version could be a scalable, efficient method to assess cognition in many different settings, including clinical trials, observational studies, healthcare, and public health.
CITATION:
M.T. Ashford ; A. Aaronson ; W. Kwang ; J. Eichenbaum ; S. Gummadi ; C. Jin ; N. Cashdollar ; E. Thorp ; E. Wragg ; K.H. Zavitz ; F. Cormack ; T. Banh ; J.M. Neuhaus ; A. Ulbricht ; M.R. Camacho ; J. Fockler ; D. Flenniken ; D. Truran ; R.S. Mackin ; M.W. Weiner ; R.L. Nosheny (2023): Unsupervised Online Paired Associates Learning Task from the Cambridge Neuropsychological Test Automated Battery (CANTAB®) in the Brain Health Registry. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.117
LETTER TO THE EDITOR: ALZHEIMER’S DISEASE-ASSOCIATED APOE Ε4 FREQUENCIES IN INDIAN POPULATION GENOMES MAY SUGGEST IMPLICATIONS IN LECANEMAB TREATMENT
B. Jolly, V. Scaria
J Prev Alz Dis 2024;2(11):525-526
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CITATION:
B. Jolly ; V. Scaria (2023): Letter to the Editor: Alzheimer’s Disease-Associated APOE ε4 Frequencies in Indian Population Genomes May Suggest Implications in Lecanemab Treatment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.122
LETTER TO THE EDITOR: CHRONIC PAIN IN MULTIPLE SITES AND DEMENTIA: A VICIOUS CYCLE?
J. Tian, G. Jones, X. Lin, Y. Zhou, A. King, J. Vickers, F. Pan
J Prev Alz Dis 2024;2(11):527-528
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CITATION:
J. Tian ; G. Jones ; X. Lin ; Y. Zhou ; A. King ; J. Vickers ; F. Pan (2023): Letter to the Editor: Chronic Pain in Multiple Sites and Dementia: A Vicious Cycle?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.120