01/2024 journal articles
THE ROOM WHERE IT HAPPENS: CLINICIAN REFLECTIONS ON RETURNING PRECLINICAL ALZHEIMER’S BIOMARKER RESULTS TO RESEARCH PARTICIPANTS
C.M. Erickson, N.A. Chin, F.B. Ketchum, M.L. Eveler, C.E. Conway, D.M. Coughlin, L.R. Clark
J Prev Alz Dis 2024;1(11):1-6
Show summaryHide summaryDisclosing Alzheimer’s disease (AD) biomarkers to research participants is a growing practice. Here, we aim to synthesize the experiences of clinicians leading preclinical AD biomarker disclosure. Semi-structured interviews were conducted individually with each of the four clinicians conducting biomarker disclosure as a part of a longitudinal, observational AD cohort study. Study clinicians emphasized the importance of participant education, having adequate time available for the disclosure visit, and forms to facilitate disclosure. To train and support future clinicians conducting AD biomarker disclosure, our study clinicians highlighted providing information about AD and biomarkers, shadowing a disclosure visit, having team debriefing sessions, and collating a frequently asked questions document. To date, this is the first characterization of clinician reflections on disclosing AD biomarker result to cognitively unimpaired research participants. As more clinicians in research or clinical settings seek to disclose AD biomarker results, best practices for training clinicians to lead disclosure are necessary.
CITATION:
C.M. Erickson ; N.A. Chin ; F.B. Ketchum ; M.L. Eveler ; C.E. Conway ; D.M. Coughlin ; L.R. Clark (2023): The Room Where It Happens: Clinician Reflections on Returning Preclinical Alzheimer’s Biomarker Results to Research Participants. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.88
DETECTION RATES OF MILD COGNITIVE IMPAIRMENT IN PRIMARY CARE FOR THE UNITED STATES MEDICARE POPULATION
Y. Liu, H. Jun, A. Becker, C. Wallick, S. Mattke
J Prev Alz Dis 2024;1(11):7-12
Show summaryHide summaryBACKGROUND: Existing evidence points to substantial gaps in detecting mild cognitive impairment in primary care but is based on limited or self-reported data. The recent emergence of disease-modifying treatments for the Alzheimer’s disease, the most common etiology of mild cognitive impairment, calls for a systematic assessment of detection rates in primary care.
OBJECTIVES: The current study aims to examine detection rates for mild cognitive impairment among primary care clinicians and practices in the United States using Medicare claims and encounter data.
DESIGN: Observational study.
SETTING: Medicare administrative data.
PARTICIPANTS: The study sample includes a total of 226,756 primary care clinicians and 54,597 practices that had at least 25 patients aged 65 or older, who were enrolled in Medicare fee-for-service or a Medicare Advantage plan between 2017 and 2019.
MEASUREMENTS: The detection rate for mild cognitive impairment is assessed as the ratio between the observed diagnosis rate of a clinician or practice as documented in the data, and the expected rate based on a predictive model.
RESULTS: The average detection rates for mild cognitive impairment is 0.08 (interquartile range=0.00-0.02) for both clinicians and practices, suggesting that only about 8% of expected cases were diagnosed on average. Only 0.1% of clinicians and practices had diagnosis rates within the expected range.
CONCLUSIONS: Mild cognitive impairment is vastly underdiagnosed, pointing to an urgent need to improve early detection in primary care.
CITATION:
Y. Liu ; H. Jun ; A. Becker ; C. Wallick ; S. Mattke ; (2023): Detection Rates of Mild Cognitive Impairment in Primary Care for the United States Medicare Population. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.131
ASSOCIATION OF MULTI-DOMAIN FACTORS WITH COGNITION IN THE UK BIOBANK STUDY
W.Y. Tan, C.A. Hargreaves, N. Kandiah, S. Hilal
J Prev Alz Dis 2024;1(11):13-21
Show summaryHide summaryBACKGROUND: 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:
W.Y. Tan ; C.A. Hargreaves ; N. Kandiah ; S. Hilal ; (2024): Association of Multi-Domain Factors with Cognition in the UK Biobank Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.3
HOW MODIFIABLE ARE MODIFIABLE DEMENTIA RISK FACTORS? A FRAMEWORK FOR CONSIDERING THE MODIFIABILITY OF DEMENTIA RISK FACTORS
L. Bransby, E. Rosenich, P. Maruff, Y.Y. Lim
J Prev Alz Dis 2024;1(11):22-37
Show summaryHide summaryMany risk factors for dementia, identified from observational studies, are potentially modifiable. This raises the possibility that targeting key modifiable dementia risk factors may reduce the prevalence of dementia, which has led to the development of dementia risk reduction and prevention strategies, such as intervention trials or dementia prevention guidelines. However, what has rarely been considered in the studies that inform these strategies is the extent to which modifiable dementia risk factors can (1) be identified by individuals, and (2) be readily modified by individuals. Characteristics of modifiable dementia risk factors such as readiness of identification and targeting, as well as when they should be targeted, can influence the design, or success of strategies for reducing dementia risk. This review aims to develop a framework for classifying the degree of modifiability of dementia risk factors for research studies. The extent to which these modifiable dementia risk factors could be modified by an individual seeking to reduce their dementia risk is determined, as well as the resources that might be needed for both risk factor identification and modification, and whether modification may be optimal in early-life (aged <45 years), midlife (aged 45-65 years) or late-life (aged >65 years). Finally, barriers that could influence the ability of an individual to engage in risk factor modification and, ultimately, dementia risk reduction are discussed.
CITATION:
L. Bransby ; E. Rosenich ; P. Maruff ; Y.Y. Lim ; (2023): How Modifiable Are Modifiable Dementia Risk Factors? A Framework for Considering the Modifiability of Dementia Risk Factors. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.119
CONSISTENCY BETWEEN TREATMENT EFFECTS ON CLINICAL AND BRAIN ATROPHY OUTCOMES IN ALZHEIMER’S DISEASE TRIALS
M. ten Kate, F. Barkhof, A.J. Schwarz
J Prev Alz Dis 2024;1(11):38-47
Show summaryHide summaryBACKGROUND: Longitudinal changes in volumetric MRI outcome measures have been shown to correlate well with longitudinal changes in clinical instruments and have been widely used as biomarker outcomes in clinical trials for Alzheimer’s disease (AD). While instances of discordant findings have been noted in some trials, especially the recent amyloid-removing therapies, the overall relationship between treatment effects on brain atrophy and clinical outcomes, and how it might depend on treatment target or mechanism, clinical instrument or imaging variable is not yet clear.
OBJECTIVE: To systematically assess the consistency and therapeutic class-dependence of treatment effects on clinical outcomes and on brain atrophy in published reports of clinical trials conducted in mild cognitive impairment (MCI) and/or AD.
DESIGN: Quantitative review of the published literature. The consistency of treatment effects on clinical and brain atrophy outcomes was assessed in terms of statistical agreement with hypothesized equal magnitude effects (e.g., 30% slowing of both) and nominal directional concordance, as a function of therapeutic class.
SETTING: Interventional randomized clinical trials.
PARTICIPANTS: MCI or AD trial participants.
INTERVENTION: Treatments included were those that involved ingestion or injection of a putatively active substance into the body, encompassing both pharmacological and controlled dietary interventions.
MEASUREMENTS: Each trial included in the analysis reported at least one of the required clinical outcomes (ADAS-Cog, CDR-SB or MMSE) and at least one of the required imaging outcomes (whole brain, ventricular or hippocampal volume).
RESULTS: Data from 35 trials, comprising 185 pairwise comparisons, were included. Overall, the 95% confidence bounds overlapped with the line of identity for 150/185 (81%) of the imaging-clinical variable pairs. The greatest proportion of outliers was found in trials of anti-amyloid antibodies that have been shown to dramatically reduce the level of PET-detectable amyloid plaques, for which only 13/33 (39%) of observations overlapped the identity line. A Deming regression calculated using all data points yielded a slope of 0.54, whereas if data points from the amyloid remover class were excluded, the Deming regression line had a slope of 0.92. Directional discordance of treatment effects was also most pronounced for the amyloid-removing class, and for comparisons involving ventricular volume.
CONCLUSION: Our results provide a frame of reference for the interpretation of clinical and brain atrophy results from future clinical trials and highlight the importance of mechanism of action in the interpretation of imaging results.
CITATION:
M. ten Kate ; F. Barkhof ; A.J. Schwarz ; (2023): Consistency between Treatment Effects on Clinical and Brain Atrophy Outcomes in Alzheimer’s Disease Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.92
INVESTIGATING THE FACTOR STRUCTURE OF THE PRECLINICAL ALZHEIMER COGNITIVE COMPOSITE AND COGNITIVE FUNCTION INDEX ACROSS RACIAL/ETHNIC, SEX, AND AΒ STATUS GROUPS IN THE A4 STUDY
M. Ruthirakuhan, M. Wood Alexander1, H. Cogo-Moreira, T. Robinson, R. Amariglio, R.F. Buckley, R.A. Sperling, W. Swardfager, S.E. Black, J.S. Rabin
J Prev Alz Dis 2024;1(11):48-55
Show summaryHide summaryBackground: Disparities in Alzheimer’s disease (AD) are well-documented among different racial/ethnic groups and between sex/genders. Neuropsychological assessment provides important information about cognitive changes and can offer valuable insights into disparities. However, neuropsychological measures must be comparable across racial/ethnic and sex/gender groups to accurately interpret disparities.
OBJECTIVES: To evaluate measurement invariance (equivalence) of the Preclinical Alzheimer Cognitive Composite (PACC) and the Cognitive Function Index across racial/ethnic, sex/gender, and β-amyloid (Aβ) status groups.
DESIGN, SETTING, PARTICIPANTS: Cross-sectional analysis of screening data from the Anti-Amyloid in Asymptomatic AD (A4) Study. The study enrolled participants aged 65-85 from sites across the United States, Canada, Australia, and Japan.
MEASUREMENTS: Participants completed the PACC and the Cognitive Function Index. Participants classified as cognitively normal also underwent a Positron Emission Tomography (PET) scan to determine Aβ status.
RESULTS: Participants self-identified as non-Hispanic White (n=5241), non-Hispanic Black (n=267), Asian (n=228), or Hispanic White (n=225) as well as male (n=2885) or female (n=3076). Among those who underwent a PET scan, 3115 were classified as Aβ- and 1309 were classified as Aβ+. We found support for a one-factor model for both the PACC and Cognitive Function Index across the full sample and in samples stratified by race/ethnicity, sex/gender, and Aβ status. The one-factor model of the PACC and Cognitive Function Index demonstrated scalar measurement invariance across racial/ethnic, sex/gender, and Aβ status groups.
CONCLUSIONS: Our findings suggest that performance on the PACC and Cognitive Function Index can be compared across the racial/ethnic, sex/gender, and Aβ status groups examined in this study.
CITATION:
M. Ruthirakuhan ; M. Wood Alexander ; H. Cogo-Moreira ; T. Robinson ; R. Amariglio ; R.F. Buckley ; R.A. Sperling ; W. Swardfager ; S.E. Black ; J.S. Rabin ; (2023): Investigating the Factor Structure of the Preclinical Alzheimer Cognitive Composite and Cognitive Function Index across Racial/Ethnic, Sex, and Aβ Status Groups in the A4 Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.98
CTAD TASK FORCE PAPER - NEUROPSYCHIATRIC SYMPTOMS IN AD: CLINICAL TRIALS TARGETING MILD BEHAVIORAL IMPAIRMENT: A REPORT FROM THE INTERNATIONAL CTAD TASK FORCE
M. Soto, P. Rosenberg, C. Ballard, B. Vellas, D. Miller, S. Gauthier, M.C. Carrillo, C. Lyketsos, Z. Ismail
J Prev Alz Dis 2024;1(11):56-64
Show summaryHide summaryThe International CTAD Task Force (TF) addressed challenges related to designing clinical trials for agitation in dementia, presenting accomplishments from the two previous TFs on neuropsychiatric symptoms (NPS). In addition, this TF proposed a paradigm shift in NPS assessment and management, presenting Mild Behavioral Impairment (MBI) as a clinical syndrome. MBI is marked by later-life emergent and persistent NPS in dementia-free older persons (ranging from cognitively unimpaired to subjective cognitive decline to mild cognitive impairment), which facilitates earlier detection and better prognostication of Alzheimer’s disease (AD). The TF has made the following recommendations for incorporation of NPS into AD preventative trials: (1) clinical trials targeting improvement in MBI symptoms should be undertaken; (2) treatment trials for MBI should be disease specific and confirm the diagnosis of participants using biomarkers; trials should include measures sensitive to cognitive changes in preclinical AD, which can serve as outcome measures, in addition to changes in biomarker levels; (3) as a first step, pharmacotherapeutic trials should address the full MBI complex as well as the specific symptoms/domains that constitute MBI; (4) clinical trials using problem-adaptation psychotherapy to target affective MBI should be considered; and (5) MBI should be considered in AD trials of disease modifying therapies. The well-validated and widely-used MBI Checklist (MBI-C) is an appropriate symptom rating scale for these studies, as it was developed specifically to identify and measure MBI in dementia-free persons. Other scales such as the Neuropsychiatric Inventory (NPI) may be used, although administration at two timepoints may be necessary to operationalize the MBI criterion of symptom persistence.
CITATION:
M. Soto ; P. Rosenberg ; C. Ballard ; B. Vellas ; D. Miller ; S. Gauthier ; M.C. Carrillo ; C. Lyketsos ; Z. Ismail (2023): CTAD Task Force Paper: Neuropsychiatric Symptoms in AD: Clinical Trials Targeting Mild Behavioral Impairment: A Report from the International CTAD Task Force. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.125
PHASE 1/2A INTRAVENOUS AND SUBCUTANEOUS OLIGOMERSPECIFIC ANTIBODY KHK6640 IN MILD TO MODERATE ALZHEIMER’S DISEASE
M. Cantillon, N. Andreasen, N. Prins
J Prev Alz Dis 2024;1(11):65-70
Show summaryHide summaryBACKGROUND: KHK6640 is a novel humanized anti-amyloid beta oligomer-specific antibody. Both KHK6640 and the mouse parent antibody E64 have demonstrated high potency and efficacy for cognitive improvement in several rodent Alzheimer’s disease models, including an anti-amyloid beta injection mouse model and in age-matched double transgenic littermates. The favorable safety and pharmacokinetic profiles of KHK6640 reported in preclinical studies warrant clinical trials in Alzheimer’s disease patients.
OBJECTIVES: We evaluated the safety, pharmacokinetics, and efficacy of intravenous and subcutaneous oligomer-specific antibody KHK6640 in treating patients with prodromal Alzheimer’s disease or mild to moderate Alzheimer’s disease.
DESIGN: Phase I/2a, multicenter, randomized, double-blind, placebo-controlled trial.
SETTING: Nine sites in Europe participated in this clinical trial.
PARTICIPANTS: 97 patients with prodromal Alzheimer’s disease or mild to moderate Alzheimer’s disease.
INTERVENTION: Single and multiple ascending intravenous and subcutaneous doses of KHK6640 in doses ranging from 0.1 mg/kg to 20 mg/kg or placebo was administered to patients monthly for six months.
MEASUREMENTS: Primary outcomes were safety including amyloid-related imaging abnormalities for edema and hemorrhage, assessed with magnetic resonance imaging. Plasma and cerebrospinal fluid samples were analyzed to investigate pharmacokinetics and KHK6640 effects on biomarkers. Cognition, brain glucose metabolism and amyloid load were exploratory outcomes.
RESULTS: No amyloid-related imaging abnormalities for edema were observed. Amyloid-related imaging abnormalities for hemorrhage were comparable to that of placebo and population background. KHK6640 exposure was approximately dose-equivalent, with a serum terminal elimination half-life of approximately 19 days. KHK6640 pharmacokinetics in serum and cerebrospinal fluid, including cerebrospinal fluid oligomers trapped by the antibody were dose related. Positive trends seen in the positron emission tomography brain glucose metabolism and amyloid load, cerebrospinal tau but cognition assessments were inconclusive, due to low numbers.
CONCLUSIONS: KHK6640 was well-tolerated across all doses, without any amyloid-related imaging abnormalities for edema, and amyloid-related imaging abnormalities for hemorrhage was as population background. The demonstrated dose-response of specific target biomarkers provides dosing guidance on dose and administration method selection for further clinical development.
CITATION:
M. Cantillon ; N. Andreasen ; N. Prins (2024): Phase 1/2a Intravenous and Subcutaneous Oligomer-Specific Antibody KHK6640 in Mild to Moderate Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.2
EXPECTANCY DOES NOT PREDICT 18-MONTH TREATMENT OUTCOMES WITH COGNITIVE TRAINING IN MILD COGNITIVE IMPAIRMENT
J.N. Motter, S.N. Rushia, M. Qian, C. Ndouli, A. Nwosu, J.R. Petrella, P.M. Doraiswamy, T.E. Goldberg, D.P. Devanand
J Prev Alz Dis 2024;1(11):71-78
Show summaryHide summaryBackground: Computerized cognitive training (CCT) has emerged as a potential treatment option for mild cognitive impairment (MCI). It remains unclear whether CCT’s effect is driven in part by expectancy of improvement.
OBJECTIVES: This study aimed to determine factors associated with therapeutic expectancy and the influence of therapeutic expectancy on treatment effects in a randomized clinical trial of CCT versus crossword puzzle training (CPT) for older adults with MCI.
DESIGN: Randomized clinical trial of CCT vs CPT with 78-week follow-up.
SETTING: Two-site study - New York State Psychiatric Institute and Duke University Medical Center.
PARTICIPANTS: 107 patients with MCI.
INTERVENTION: 12 weeks of intensive training with CCT or CPT with follow-up booster training over 78 weeks.
MEASUREMENTS: Patients rated their expectancies for CCT and CPT prior to randomization.
RESULTS: Patients reported greater expectancy for CCT than CPT. Lower patient expectancy was associated with lower global cognition at baseline and older age. Expectancy did not differ by sex or race. There was no association between expectancy and measures of everyday functioning, hippocampus volume, or apolipoprotein E genotype. Expectancy was not associated with change in measures of global cognition, everyday functioning, and hippocampus volume from baseline to week 78, nor did expectancy interact with treatment condition.
CONCLUSIONS: While greater cognitive impairment and increased age was associated with low expectancy of improvement, expectancy was not associated with the likelihood of response to treatment with CPT or CCT.
CITATION:
J.N. Motter ; S.N. Rushia ; M. Qian ; C. Ndouli ; A. Nwosu ; J.R. Petrella ; P.M. Doraiswamy ; T.E. Goldberg ; D.P. Devanand ; (2023): Expectancy Does Not Predict 18-month Treatment Outcomes with Cognitive Training in Mild Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.62
DIGITAL CLOCK DRAWING AS AN ALZHEIMER’S DISEASE SUSCEPTIBILITY BIOMARKER: ASSOCIATIONS WITH GENETIC RISK SCORE AND APOE IN OLDER ADULTS
L.I. Thompson, M. Cummings, S. Emrani, D.J. Libon, A. Ang, C. Karjadi, R. Au, C. Liu
J Prev Alz Dis 2024;1(11):79-87
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) is the leading cause of dementia in older adults, but most people are not diagnosed until significant neuronal loss has likely occurred along with a decline in cognition. Non-invasive and cost-effective digital biomarkers for AD have the potential to improve early detection.
OBJECTIVE: We examined the validity of DCTclockTM (a digitized clock drawing task) as an AD susceptibility biomarker.
DESIGN: We used two primary independent variables, Apolipoprotein E (APOE) ε4 allele carrier status and polygenic risk score (PRS). We examined APOE and PRS associations with DCTclockTM composite scores as dependent measures.
SETTING: We used existing data from the Framingham Heart Study (FHS), a community-based study with the largest dataset of digital clock drawing data to date.
PARTICIPANTS: The sample consisted of 2,398 older adults ages 60-94 with DCTclockTM data (mean age of 72.3, 55% female and 92% White).
MEASUREMENTS: PRS was calculated using 38 variants identified in a recent large genome-wide association study (GWAS) and meta-analysis of late-onset AD (LOAD).
RESULTS: Results showed that DCTclockTM performance decreased with advancing age, lower education, and the presence of one or more copies of APOE ε4. Lower DCTclockTM Total Score as well as lower composite scores for Information Processing Speed (both command & copy conditions) and Drawing Efficiency (command condition) were significantly associated with higher PRS levels and more copies of APOE ε4. APOE and PRS associations displayed similar effect sizes in both men and women.
CONCLUSIONS: Our results indicate that higher AD genetic risk is associated with poorer DCTclockTM performance in older adults without dementia. This is the first study to demonstrate significant differences in clock drawing performance on the basis of APOE status or PRS.
CITATION:
L.I. Thompson ; M. Cummings ; S. Emrani ; D.J. Libon ; A. Ang ; C. Karjadi ; R. Au ; C. Liu ; (2023): Digital Clock Drawing as an Alzheimer’s Disease Susceptibility Biomarker: Associations with Genetic Risk Score and APOE in Older Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.48
LIFESTYLE AND SOCIOECONOMIC TRANSITION AND HEALTH CONSEQUENCES OF ALZHEIMER’S DISEASE AND OTHER DEMENTIAS IN GLOBAL, FROM 1990 TO 2019
Y. Cui, W. Yang, J. Shuai, Y. Ma, Y. Yan
J Prev Alz Dis 2024;1(11):88-96
Show summaryHide summaryBackground: Previous studies only focused on changes in the global age-specific incidence and mortality for Alzheimer’s disease and other dementias, failed to distinguish between cohort and period effects, and did not discuss risk factors separately.
Methods: In this study, Alzheimer’s disease disability-adjusted life years (DALYs) data to estimate the burden by gender, age, locations, and social-demographic status for 21 regions from 1990 to 2019. Additionally, trend analysis was performed using the age-period-cohort (APC) model and Join-point model.
Results: In most regions, indicators (incidence, mortality, and DALYs) increased steadily with socio-demographic index(SDI) increased. The age effects for Alzheimer’s disease and other dementias showed a significant increase from 40 to 95 years. The cohort effects rate ratios (RRs) had a rapid reduction attributed to smoking, high fasting plasma glucose, and high body mass index (BMI).
Conclusions: Countries in middle-low and low SDI regions have higher levels of risk factor exposure. As a result, rapid and effective government responses are necessary to control dementia risk factors and reduce the disease burden in these countries.
CITATION:
Y. Cui ; W. Yang ; J. Shuai ; Y. Ma ; Y. Yan ; (2023): Lifestyle and Socioeconomic Transition and Health Consequences of Alzheimer’s Disease and Other Dementias in Global, from 1990 to 2019. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.63
BURDEN OF ILLNESS IN PEOPLE WITH ALZHEIMER’S DISEASE: A SYSTEMATIC REVIEW OF EPIDEMIOLOGY, COMORBIDITIES AND MORTALITY
K.L. Lanctôt, J. Hviid Hahn-Pedersen, C.S. Eichinger, C. Freeman, A. Clark, L.R.S. Tarazona, J. Cummings
J Prev Alz Dis 2024;1(11):97-107
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide, and an updated quantification of its impact on morbidity, disability, and mortality is warranted. We conducted a systematic literature review, focusing on the past decade, to characterize AD and assess its impact on affected individuals.
METHODS: Searches of Embase, MEDLINE, and the Cochrane Library were conducted on August 7, 2020 and updated on November 10, 2021. Observational studies from any country reporting incidence, prevalence, comorbidities, and/or outcomes related to disability and mortality/life expectancy, in people with mild cognitive impairment (MCI) due to AD, or mild, moderate, or severe AD dementia, were considered relevant.
RESULTS: Data were extracted from 88 studies (46 incidence/prevalence; 44 comorbidities; 25 mortality-/disability-related outcomes), mostly from Europe, the USA, and Asia. AD dementia diagnosis was confirmed using biomarkers in only 6 studies. Estimated 5-year mortality in AD was 35%, and comorbidity prevalence estimates varied widely (hypertension: 30.2–73.9%; diabetes: 6.0–24.3%; stroke: 2.7–13.7%). Overall, people with AD dementia were more likely to have cardiovascular disease or diabetes than controls, and 5-year mortality in people with AD dementia was double that in the age- and year-matched general population (115.0 vs 60.6 per 1,000 person-years).
CONCLUSIONS: AD is associated with excess morbidity and mortality. Future longitudinal studies of population aging, incorporating biomarker assessment to confirm AD diagnoses, are needed to better characterize the course of MCI due to AD and AD dementia.
CITATION:
K.L. Lanctôt ; J. Hviid Hahn-Pedersen ; C.S. Eichinger ; C. Freeman ; A. Clark ; L.R.S. Tarazona ; J. Cummings (2023): Burden of Illness in People with Alzheimer’s Disease: A Systematic Review of Epidemiology, Comorbidities and Mortality. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.61
MODIFIABLE RISK FACTORS FOR ACCELERATED DECLINE IN PROCESSING SPEED: RESULTS FROM THREE DUTCH POPULATION COHORTS
E. Jaarsma, A. Nooyens, A.A.L. Kok, S. Köhler, M. van Boxtel, W.M.M. Verschuren, M. Huisman
J Prev Alz Dis 2024;1(11):108-116
Show summaryHide summaryBACKGROUND: Several lifestyle, cardiovascular and psychosocial factors are associated with risk of cognitive decline and dementia. We studied the independent associations of a broad set of modifiable risk factors with decline in processing speed in three large population-based cohorts with up to 23 years of follow-up.
METHODS: We used data of 9,666 participants from the Doetinchem Cohort Study, the Longitudinal Aging Study Amsterdam, and the Maastricht Aging Study. Decline in processing speed was measured with the letter digit substitution task or the alphabet coding task and modeled using quadratic latent growth curves. Associations of modifiable risk factors with level and rate of decline in processing speed were investigated by estimating associations with level of processing speed at different centering ages.
RESULTS: Latent growth curves showed that decline in processing speed accelerated with age. Smoking, not drinking alcohol and depressive symptoms were associated with a lower level of processing speed in all cohorts. In two of the cohorts, more physical activity, drinking more than two glasses of alcohol per day, higher BMI and diabetes were associated with a lower level of processing speed. Depressive symptoms and diabetes were also associated with faster decline in processing speed.
CONCLUSION: Several modifiable risk factors are associated with the level of processing speed in older age, while few are also related to the rate of decline.
CITATION:
E. Jaarsma ; A. Nooyens ; A.A.L. Kok ; S. Köhler ; M. van Boxtel ; W.M.M. Verschuren ; M. Huisman ; (2023): Modifiable Risk Factors for Accelerated Decline in Processing Speed: Results from Three Dutch Population Cohorts. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.64
RELATIONSHIPS OF HYPNOTICS WITH INCIDENT DEMENTIA AND ALZHEIMER’S DISEASE: A LONGITUDINAL STUDY AND META-ANALYSIS
J.-H. Hou, S.-L. Sun, C.-C. Tan, Y.-M. Huang, L. Tan, for the Alzheimer’s Disease Neuroimaging Initiative, W. Xu
J Prev Alz Dis 2024;1(11):117-129
Show summaryHide summaryBACKGROUND: Evidence describing the association between hypnotics use and dementia risk is conflicting. It is unknown if the controversy is related to the type or dose of hypnotics or if hypnotics affect different populations.
OBJECTIVES: We sought to derive lessons learned and future projections based on evidence from longitudinal studies.
MEASUREMENTS: In the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, 1,543 older adults without dementia (mean age = 73.3 years, female = 45%) were followed for four years. The association between hypnotics and the risk of Alzheimer’s disease (AD) was investigated using Cox proportional hazards regressions. Next, electronic databases were searched until March 2022 to conduct the evidence synthesis of the associations of hypnotics with incident risk of dementia.
RESULTS: In the ADNI cohort, ever use of hypnotics was associated with an increased risk of AD (hazard ratio = 1.96, 95% confidence intervals = 1.23-3.11, p < 0.01). This association was significant for benzodiazepines and Z-drugs but not for melatonin. The association was stronger in long-term (more than one year) users and those with high cumulative doses. A meta-analysis of 26 longitudinal studies with 3,942,018 participants revealed a correlation between the use of hypnotics and the risk of dementia (relative risk = 1.23, 95% confidence intervals = 1.13-1.33, p < 0.001, median risk difference = 4%). It is a linear dose-response relationship, if a person takes the daily recommended dose for 100 days, their risk of developing dementia increases by 5% relative to non-users. According to subgroup analyses, neither association was significant among patients with a history of insomnia.
CONCLUSIONS: Individuals who use hypnotics, especially high-dose or long-term users, are at a higher risk of dementia and AD. The main issue with conclusion credibility is heterogeneity.
CITATION:
J.-H. Hou ; S.-L. Sun ; C.-C. Tan ; Y.-M. Huang ; L. Tan ; for the Alzheimer’s Disease Neuroimaging Initiative ; W. Xu ; (2023): Relationships of Hypnotics with Incident Dementia and Alzheimer’s Disease: A Longitudinal Study and Meta-Analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.78
ASSOCIATION OF BALANCE IMPAIRMENT WITH RISK OF INCIDENT DEMENTIA AMONG OLDER ADULTS
H.J. Kim, S. Jeong, Y.H. Oh, M.J. Suh
J Prev Alz Dis 2024;1(11):130-137
Show summaryHide summaryBACKGROUND: A growing body of data suggests that balance impairment may be linked to the onset of dementia.
OBJECTIVES: However, a large-scale epidemiologic investigation is needed to clarify its association in older adults.
DESIGN: A retrospective-prospective hybrid database.
SETTING: Cox proportional hazards regression model was used to assess the relationship between balance impairment and the risk of incident dementia, and the results were provided as adjusted hazard ratios (aHR) with 95% confidence intervals (CI). All participants were tracked until the date of incident dementia, death, or 31 December 2019 whichever came first.
PARTICIPANTS: We analyzed 143,788 older adults who had at least one health screening between 2009 and 2019 from the Korea National Health Insurance Service-Senior Cohort.
MEASUREMENTS: A total of 3,774 cases of dementia were discovered throughout 850,425 person-years of follow-up investigation. Balance impairment was associated with a risk of dementia compared to those without balance impairment (adjusted hazard ratio [aHR] 1.83; 95% CI, 1.69-2.00; P value <0.001).
RESULTS: Risks of the Alzheimer’s disease (aHR, 1.80; 95% CI, 1.65-1.96; P for trend <0.001) and the vascular dementia (aHR, 2.94; 95% CI, 1.89-4.58; P for trend <0.001) showed comparable trends and findings.
CONCLUSIONS: Balance impairment was found to be independently associated with an increased risk of dementia in older adults.
CITATION:
H.J. Kim ; S. Jeong ; Y.H. Oh ; M.J. Suh ; (2023): Association of Balance Impairment with Risk of Incident Dementia among Older Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.79
HIGH-FAT DIET-INDUCED DIABETIC CONDITIONS EXACERBATE COGNITIVE IMPAIRMENT IN A MOUSE MODEL OF ALZHEIMER’S DISEASE VIA A SPECIFIC TAU PHOSPHORYLATION PATTERN
Y. Ito, S. Takeda, T. Nakajima, A. Oyama, H. Takeshita, K. Miki, Y. Takami, Y. Takeya, M. Shimamura, H. Rakugi, R. Morishita
J Prev Alz Dis 2024;1(11):138-148
Show summaryHide summaryBACKGROUND: Epidemiological evidence has demonstrated a clear association between diabetes mellitus and increased risk of Alzheimer’s disease (AD). Cerebral accumulation of phosphorylated tau aggregates, a cardinal neuropathological feature of AD, is associated with neurodegeneration and cognitive decline. Clinical and experimental studies indicate that diabetes mellitus affects the development of tau pathology; however, the underlying molecular mechanisms remain unknown.
OBJECTIVE: In the present study, we used a unique diabetic AD mouse model to investigate the changes in tau phosphorylation patterns occurring in the diabetic brain.
DESIGN: Tau-transgenic mice were fed a high-fat diet (n = 24) to model diabetes mellitus. These mice developed prominent obesity, severe insulin resistance, and mild hyperglycemia, which led to early-onset neurodegeneration and behavioral impairment associated with the accumulation of hyperphosphorylated tau aggregates.
RESULTS: Comprehensive phosphoproteomic analysis revealed a unique tau phosphorylation signature in the brains of mice with diabetic AD. Bioinformatic analysis of the phosphoproteomics data revealed putative tau-related kinases and cell signaling pathways involved in the interaction between diabetes mellitus and AD.
CONCLUSION: These findings offer potential novel targets that can be used to develop tau-based therapies and biomarkers for use in AD.
CITATION:
Y. Ito ; S. Takeda ; T. Nakajima ; A. Oyama ; H. Takeshita ; K. Miki ; Y. Takami ; Y. Takeya ; M. Shimamura ; H. Rakugi ; R. Morishita ; (2023): High-Fat Diet-Induced Diabetic Conditions Exacerbate Cognitive Impairment in a Mouse Model of Alzheimer’s Disease Via a Specific Tau Phosphorylation Pattern. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.85
COMPUTERIZED COGNITIVE TRAINING IN MILD COGNITIVE IMPAIRMENT: FINDINGS IN AFRICAN AMERICANS AND CAUCASIANS
A. Nwosu, M. Qian, J. Phillips, C.A. Hellegers, S. Rushia, J. Sneed, J.R. Petrella, T.E. Goldberg, D.P. Devanand, P.M. Doraiswamy
J Prev Alz Dis 2024;1(11):149-154
Show summaryHide summaryBACKGROUND: African Americans with MCI may be at increased risk for dementia compared to Caucasians. The effect of race on the efficacy of cognitive training in MCI is unclear.
METHODS: We used data from a two-site, 78-week randomized trial of MCI comparing intensive, home-based, computerized training with Web-based cognitive games or Web-based crossword puzzles to examine the effect of race on outcomes. The study outcomes were changes from baseline in cognitive and functional scales as well as MRI-measured changes in hippocampal volume and cortical thickness. Analyses used linear models adjusted for baseline scores. This was an exploratory study.
RESULTS: A total of 105 subjects were included comprising 81 whites (77.1%) and 24 African Americans (22.8%). The effect of race on the change from baseline in ADAS-Cog-11 was not significant. The effect of race on change from baseline to week 78 in the Functional Activities Questionnaire (FAQ) was significant with African American participants’ FAQ scores showing greater improvements at weeks 52 and 78 (P = 0.009, P = 0.0002, respectively) than white subjects. Within the CCT cohort, FAQ scores for African American participants showed greater improvement between baseline and week 78, compared to white participants randomized to CCT (P = 0.006). There was no effect of race on the UPSA. There was no effect of race on hippocampal or cortical thickness outcomes.
CONCLUSIONS: Our preliminary findings suggest that web-based cognitive training programs may benefit African Americans with MCI at least as much as Caucasians, and highlight the need to further study underrepresented minorities in AD prevention trials. (Supported by the National Institutes of Health, National Institute on Aging; ClinicalTrials.gov number, NCT03205709.)
CITATION:
A. Nwosu ; M. Qian ; J. Phillips ; C.A. Hellegers ; S. Rushia ; J. Sneed ; J.R. Petrella ; T.E. Goldberg ; D.P. Devanand ; P.M. Doraiswamy ; (2023): Computerized Cognitive Training in Mild Cognitive Impairment: Findings in African Americans and Caucasians. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.80
ESTIMATES OF CURRENT CAPACITY FOR DIAGNOSING ALZHEIMER’S DISEASE IN SWEDEN AND THE NEED TO EXPAND SPECIALIST NUMBERS
S. Mattke, A. Gustavsson, L. Jacobs, S. Kern, S. Palmqvist, M. Eriksdotter, I. Skoog, B. Winblad, A. Wimo, L. Jönsson
J Prev Alz Dis 2024;1(11):155-161
Show summaryHide summaryBACKGROUND: The emergence of disease-modifying Alzheimer’s (AD) treatments provides new hope to patients and families but concerns have been raised about the preparedness of healthcare systems to provide timely access to such treatments because of a combination of a complex diagnostic process and a large prevalent pool.
OBJECTIVES: We assess the preparedness of Sweden, a high-income country known for its dementia-friendly policies, to diagnose AD patients eligible for treatment within a six-month window, given current capacity for specialist evaluations and biomarker testing. We calculate the investment requirements for Sweden to achieve this target over a timeframe of 20 years.
DESIGN: Desk research to identify data for population, mortality, disease burden, cost of services and current capacity, expert consultation to inform assumptions about patient journey, and use of a Markov model to predict waiting times. The model simulates the patients’ journey through different evaluation stages: initial evaluation by a primary care specialist, neurocognitive testing by an AD specialist, and confirmatory biomarker testing with PET scanning or cerebrospinal fluid (CSF) testing. The model assumes specialist appointments and PET scans are capacity constrained, and patients progress from cognitively normal to MCI and from MCI to dementia in the resulting waiting times.
MEASUREMENTS: Projected waiting times for diagnosis of eligibility for disease-modifying Alzheimer’s treatment from 2023 to 2042 assuming current capacity, assuming 20% of Swedish residents aged 60 years and above would seek an evaluation for cognitive decline. Investments required to scale capacity up to reach target of providing diagnosis within six months on average.
RESULTS: Initial average waiting times for AD specialist appointments would be around 21 months in 2023 and remain around 55 months through 2042, as demand would continue to outstrip supply throughout the 20-year model horizon. Waiting times for biomarker testing would be stable at less than four weeks, as patients would be held up in the queue for their first specialist consultations, and use of CSF testing is widely accepted in Sweden. An additional 25% of AD specialists would have to be added above the current growth trend to reduce waiting times to less than 6 months at an average annual cost of approximately 805 million SEK. The increased cost of volume of biomarker testing would amount to about 106 million SEK per year.
CONCLUSIONS: At current capacity, the Swedish healthcare system is unable to provide timely diagnosis of patients eligible for disease-modifying AD treatment. Although future diagnostic technologies, such as digital cognitive assessments and blood tests for the AD pathology, might decrease demand for capacity-constrained services, substantial investments will be required to meet a target of less than six months of waiting time for a diagnosis.
CITATION:
S. Mattke ; A. Gustavsson ; L. Jacobs ; S. Kern ; S. Palmqvist ; M. Eriksdotter ; I. Skoog ; B. Winblad ; A. Wimo ; L. Jönsson ; (2023): Estimates of Current Capacity for Diagnosing Alzheimer’s Disease in Sweden and the Need to Expand Specialist Numbers. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.94
COGNITIVE PERFORMANCE AND INCIDENT ALZHEIMER’S DEMENTIA IN MEN VERSUS WOMEN
I. Liampas, V. Siokas, C.G. Lyketsos, E. Dardiotis
J Prev Alz Dis 2024;1(11):162-170
Show summaryHide summaryBACKGROUND: The utility of neuropsychological measurements as forerunners of Alzheimer’s Disease Dementia (AD) in individuals with normal cognition or mild cognitive impairment (MCI) is undeniable.
OBJECTIVES: To assess the differential prognostic value of cognitive performance in older men versus women.
DESIGN: Longitudinal analysis of data acquired from the National Alzheimer’s Coordinating Center Uniform Data Set.
SETTINGS: Data on older adults (≥60 years) were derived from 43 National Institute on Aging - funded Alzheimer’s Disease Research Centers.
PARTICIPANTS: 10,073 cognitively unimpaired (CU) older adults followed for 5.5±3.8 years and 3,925 participants with amnestic MCI monitored for 3.5±2.8 years.
MEASUREMENTS: The domains of episodic memory, verbal fluency, naming, attention, processing speed and executive function were assessed. Cox proportional hazards models examined associations between individual cognitive domains and AD incidence separately for each participant set. CU and MCI. These predictive models featured individual neuropsychological measures, sex, neuropsychological measure by sex interactions, as well as a number of crucial covariates.
RESULTS: Episodic memory and verbal fluency were differentially related to future AD among CU individuals, explaining a larger proportion of risk variance in women compared to men. On the other hand, naming, attention and executive function were differentially related to future AD among participants with MCI, accounting for a greater fraction of risk variance in men than women.
CONCLUSION: Cognitive performance is differentially related to risk of progressing to AD in men versus women without dementia.
CITATION:
I. Liampas ; V. Siokas ; C.G. Lyketsos ; E. Dardiotis (2023): Cognitive Performance and Incident Alzheimer’s Dementia in Men Versus Women. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.90
GLOBAL ENERGY METABOLISM DEFICIT IN ALZHEIMER DISEASE BRAIN
V. Patel, J. Mill, O.C. Okonkwo, S. Salamat, L. Li, T. Raife
J Prev Alz Dis 2024;1(11):171-178
Show summaryHide summaryBACKGROUND: The understanding of Alzheimer’s disease (AD) has been dominated by the amyloid hypothesis. However, therapies targeting beta-amyloid have largely failed, generating interest in other potential pathogenic factors including energy metabolism.
OBJECTIVES: To interrogate canonical energy metabolism pathways from human prefrontal cortical tissue samples obtained from necropsy comparing AD and control.
DESIGN, SETTING, AND PARTICIPANTS: Postmortem pre-frontal cortical tissue from 10 subjects histologically diagnosed with AD and 10 control (CTRL) subjects was subjected to untargeted metabolomics to interrogate energy metabolism pathways. The samples were matched by age, sex, and post-mortem interval.
Metabolite Measurements: Untargeted metabolomics analyses were via Metabolon®.
RESULTS: Glucose-derived energy metabolites in the glycolytic and pentose phosphate pathway and the ketone body β-hydroxybutyrate were uniformly decreased in AD brain vs. CTRL brain.
CONCLUSION: This pilot study aimed to identify energy metabolism abnormalities using untargeted brain metabolomics in two independent subject cohorts. Our study revealed a pattern of global energy deficit in AD brain, supporting a growing body of evidence of deficient energy metabolism in AD.
CITATION:
V. Patel ; J. Mill ; O.C. Okonkwo ; S. Salamat ; L. Li ; T. Raife ; (2023): Global Energy Metabolism Deficit in Alzheimer Disease Brain. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.91
PROJECTED SAVINGS TO CANADIAN PROVINCIAL BUDGETS FROM REDUCED LONG-TERM CARE HOME UTILIZATION DUE TO A DISEASE-MODIFYING ALZHEIMER’S TREATMENT
H. Jun, Z. Shi, S. Mattke
J Prev Alz Dis 2024;1(11):179-184
Show summaryHide summaryBACKGROUND: A disease-modifying Alzheimer’s treatment could provide budgetary savings to Canadian provinces from a reduction in long-term care home use, yet we do not know the magnitude of those potential savings.
OBJECTIVE: We project savings to each Canadian province’s budget from 2023 to 2043.
DESIGN: Annual savings are projected using a Markov model. We account for reduction in long-term care home use and in use of Alternative Level of Care (ALC) beds, which are hospital beds occupied by care home-eligible patients on the wait list for admission.
RESULTS: A treatment that delays disease progression by 40% is projected to avoid 142,507 long-term care home and ALC years, resulting in $17.2 billion cumulative savings across all Canadian provinces, a 21% relative reduction among treatment eligible patients. Average per capita savings were $1,132, ranging from $734 (Alberta) to $2,895 (Prince Edward Island). Cumulative savings could increase to $22.7 billion with enhanced triage of patients in primary care stages and to $25.6 billion if all capacity constraints for diagnosis and treatment were removed.
CONCLUSION: A disease-modifying treatment could create budgetary savings from lower long-term care home use, offsetting part of the treatment cost. With the increasing demand for long-term care home beds and the high rates of patients being held in hospitals while wait-listed, such a treatment could additionally provide relief to the overburdened long-term care system in Canada.
CITATION:
H. Jun ; Z. Shi ; S. Mattke ; (2023): Projected Savings to Canadian Provincial Budgets from Reduced Long-Term Care Home Utilization Due to a Disease-Modifying Alzheimer’s Treatment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.95
DATA-DRIVEN THRESHOLDING STATISTICALLY BIASES ATN PROFILING ACROSS COHORT DATASETS
Y. Salimi, D. Domingo-Fernández, M. Hofmann-Apitius, C. Birkenbihl, for the Alzheimer’s Disease Neuroimaging Initiative, the Japanese Alzheimer’s Disease Neuroimaging Initiative, the Alzheimer’s Disease Repository Without Borders Investigators, for the European Prevention of Alzheimer’s Disease (EPAD) Consortium
J Prev Alz Dis 2024;1(11):185-195
Show summaryHide summaryBACKGROUND: While the amyloid/tau/neurodegeneration (ATN) framework has found wide application in Alzheimer’s disease research, it is unclear if thresholds obtained using distinct thresholding methods are concordant within the same dataset and interchangeable across cohorts.
OBJECTIVES: To investigate the robustness of data-driven thresholding methods and ATN profiling across cohort datasets.
DESIGN AND SETTING: We evaluated the impact of thresholding methods on ATN profiles by applying five commonly-used methodologies across cohort datasets. We assessed the generalizability of disease patterns discovered within ATN profiles by clustering individuals from different cohorts who were assigned to the same ATN profile.
PARTICIPANTS AND MEASUREMENTS: Participants with available CSF amyloid-β 1-42, phosphorylated tau, and total tau measurements were included from eleven AD cohort studies.
RESULTS: We observed high variability among obtained ATN thresholds, both across methods and datasets that impacted the resulting profile assignments of participants significantly. Clustering participants from different cohorts within the same ATN category indicated that identified disease patterns were comparable across most cohorts and biases introduced through distinct thresholding and data representations remained insignificant in most ATN profiles.
CONLUSION: Thresholding method selection is a decision of statistical relevance that will inevitably bias the resulting profiling and affect its sensitivity and specificity. Thresholds are likely not directly interchangeable between independent cohorts. To apply the ATN framework as an actionable and robust profiling scheme, a comprehensive understanding of the impact of used thresholding methods, their statistical implications, and a validation of results is crucial.
CITATION:
Y. Salimi ; D. Domingo-Fernández ; M. Hofmann-Apitius ; C. Birkenbihl ; for the Alzheimer’s Disease Neuroimaging Initiative, ; the Japanese Alzheimer’s Disease Neuroimaging Initiative, ; the Alzheimer’s Disease Repository Without Borders Investigators‡, for the European Prevention of Alzheimer’s Disease (EPAD) Consortium ; (2023): Data-Driven Thresholding Statistically Biases ATN Profiling across Cohort Datasets. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.100
ALZHEIMER’S DISEASE AND AGING ASSOCIATION: IDENTIFICATION AND VALIDATION OF RELATED GENES
T. Liu, K. Hou, J. Li, T. Han, S. Liu, . Wei
J Prev Alz Dis 2024;1(11):196-213
Show summaryHide summaryBACKGROUND: Aging is considered a key risk factor for Alzheimer’s disease (AD). This study aimed to identify and validate potential aging-related genes associated with AD using bioinformatics analysis.
METHODS: Datasets GSE36980 and GSE5281 were selected to screen differentially expressed genes (DEGs), and the immune cell correlation analysis and GSEA analysis of DEGs were performed. The intersection with senescence genes was taken as differentially expressed senescence-related genes (DESRGs), and the GSE44770 dataset was used for further validation. The potential biological functions and signaling pathways were determined by GO and KEGG, and the hub genes were identified by 12 algorithms in Cytohubba. The expression of 10 hub genes in different brain regions was determined and single-cell sequencing analysis was performed, and diagnostic genes were further screened by gene expression and receiver operating characteristic (ROC) curve. Finally, a miRNA-gene network of diagnostic genes was constructed and targeted drug prediction was performed.
RESULTS: A total of 2137 DEGs were screened from the GSE36980 and GSE5281 datasets, and 278 SRGs were identified from the CellAge database. The overlapping DEGs and SRGs constituted 29 DESRGs, including 14 senescence suppressor genes and 15 senescence inducible genes. The top 10 hub genes, including MDH1, CKB, PSMD14, SMARCA4, PEBP1, DDB2, ITPKB, ATF7IP, YAP1, and EWSR1 were screened. Furthermore, four diagnostic genes were identified: PMSD14, PEBP1, ITPKB, and ATF7IP. The ROC analysis showed that the respective area under the curves (AUCs) of PMSD14, PEBP1, ITPKB, and ATF7IP were 0.732, 0.701, 0.747, and 0.703 in the GSE36980 dataset and 0.870, 0.817, 0.902, and 0.834 in the GSE5281 dataset. In the GSE44770 dataset, PMSD14 (AUC, 0.838) and ITPKB (AUC, 0.952) had very high diagnostic values in the early stage of AD. Finally, based on these diagnostic genes, we found that the drug Abemaciclib is a targeted drug for the treatment of age-related AD. Flutamide can aggravate aging-related AD.
CONCLUSION: The results of this study suggest that cellular SRGs might play an important role in AD. PMSD14, PEBP1, ITPKB, and ATF7IP have the potential as specific biomarkers for the early diagnosis of AD.
CITATION:
T. Liu ; K. Hou ; J. Li ; T. Han ; S. Liu ; J. Wei ; (2023): Alzheimer’s Disease and Aging Association: Identification and Validation of Related Genes. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.101
CHINA ALZHEIMER’S DISEASE AND NEURODEGENERATIVE DISORDER RESEARCH (CANDOR) -A PROSPECTIVE COHORT STUDY FOR ALZHEIMER’S DISEASE AND VASCULAR COGNITIVE IMPAIRMENT
S. Li, H. Dong, Y. Wang, S. Wang, X. Lv, M. Dong, S. Tian, J. Shi
J Prev Alz Dis 2024;1(11):214-221
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) and vascular cognitive impairment (VCI) are the two main causes of dementia. AD and VCI share similar symptoms of cognitive decline and may be attributable to similar risk factors. Establishing a prospective cohort to compare VCI and AD would help to understand vascular risk factors related to dementia.
OBJECTIVES: China Alzheimer’s disease and Neurodegenerative Disorder Research (CANDOR) study is a prospective multicenter cohort study. It aims to study the similarities and differences between AD and post stroke cognitive impairment (PSCI) in neuroimaging changes, disease progression, and multiple omics studies.
DESIGN: This is an ongoing study. From July 31, 2019, to August 1, 2022, we recruited 1449 participants with ages between 40 and 100 years. The cohort included three groups: AD group, PSCI group, and normal cognitive (NC) group. Data were collected in face-to-face interviews at baseline, and will be followed up every year for 4 years. The PSCI group had additional follow-ups at 3-month and 6-month after enrollment. Brain Magnetic Resonance Imaging (MRI) included high-resolution sequences for intracranial arteries. Cognitive assessments and follow-up information will be prospectively collected. Biological specimens including blood and urine at baseline were collected and tested.
PARTICIPANTS: The targeted sample size of PSCI group was 500, AD group with 600 and NC group with 2000. There were 1449 participants enrolled. Include 508 participants were in NC group, 387 in AD group and 554 in PSCI group.
MEASUREMENTS: Demographics, clinical parameters, and medical examinations were collected and performed. Cognitive assessment was performed to assess all cognitive domains including memory, language, executive function, and orientation function.
CONCLUSIONS: The CANDOR study is a prospective cohort study. Data from this cohort provide us an opportunity to investigate the contribution of vascular factors to dementia pathogenesis.
CITATION:
S. Li ; H. Dong ; Y. Wang ; S. Wang ; X. Lv ; M. Dong ; S. Tian ; J. Shi ; (2023): China Alzheimer’s Disease and Neurodegenerative Disorder Research (CANDOR) -A Prospective Cohort Study for Alzheimer’s Disease and Vascular Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.97
THE THERAPEUTIC EFFECTS OF NONINVASIVE BRAIN STIMULATION COMBINED WITH COGNITIVE TRAINING IN ELDERS WITH ALZHEIMER’S DISEASE OR AMNESIC MILD COGNITIVE IMPAIRMENT
J.-Y. Wang, J.-Y. Qin, J.-Y. Ye, W.-T. Li, M.-Q.-Z. Tong, H. Ouyang, F.-X. Yan
J Prev Alz Dis 2024;1(11):222-229
Show summaryHide summaryBACKGROUND: Recent studies have indicated that noninvasive brain stimulation combined with cognitive interval (NIBS-CI) improved cognitive function in people with Alzheimer’s disease (AD) or Amnesic mild cognitive impairment (a-MCI). While previous interventions have demonstrated that a single targeted cognitive intervention can improve cognitive function, the outcomes of using both interventions simultaneously are less well-established. Therefore, this study aims to perform a meta-analysis to determine the effectiveness of NIBS-CI in treating cognitive impairment associated with AD and a-MCI, with the goal of obtaining novel insights into this combined intervention.
METHODS: PubMed, Web of Science, ProQuest and Central Cochrane library databases were searched up to December 2022. The primary cognitive outcomes were extracted from the included article. A mean difference (MD) and standardized mean difference (SMD) with a 95% confidence interval were calculated by using random-effect models.
RESULTS: Twelve studies with a total of 587 AD patients were included. The findings demonstrated that NIBS-CI significantly improved cognitive function of AD patients in cognitive outcomes (SMD = -0.52, 95%CI (-0. 93, -0.11)) and ADAS-COG (MD = -1.16, 95%CI (-1.69, -0.63)). The pooled results showed that NIBS-CI did not improve cognitive function of AD patients in short-time memory (SMD = 0.057, 95%CI (-0.13, 0.25), P = 0.56) and long-time memory (SMD = 0.001, 95%CI (-0.20, 0.20), P = 0.99).
CONCLUSIONS: There is evidence for a positive effect of NIBS-CI on overall cognitive function of AD and a-MCI. Considering the limited sample size, it is important to interpret the findings related to memory with caution. To obtain more robust results, future studies should be conducted with larger sample sizes and incorporate objective neurophysiological and neuroimaging tools. These methodological enhancements will allow for a better understanding of the therapeutic targets and provide a more comprehensive assessment of the effects of NIBS-CI treatment.
CITATION:
J.-Y. Wang ; J.-Y. Qin ; J.-Y. Ye ; W.-T. Li ; M.-Q.-Z. Tong ; H. Ouyang ; F.-X. Yan ; (2024): The Therapeutic Effects of Noninvasive Brain Stimulation Combined with Cognitive Training in Elders with Alzheimer’s Disease or Amnesic Mild Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.1
ASSOCIATION OF BLOOD MICRORNA EXPRESSION AND POLYMORPHISMS WITH COGNITIVE AND BIOMARKER CHANGES IN OLDER ADULTS
A. Sadlon, P. Takousis, E. Evangelou, I. Prokopenko, P. Alexopoulos, C.-M. Udeh-Momoh, G. Price, L. Middleton, R. Perneczky, or the Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2024;1(11):230-240
Show summaryHide summaryBACKGROUND: Identifying individuals before the onset of overt symptoms is key in the prevention of Alzheimer’s disease (AD).
OBJECTIVES: Investigate the use of miRNA as early blood-biomarker of cognitive decline in older adults.
DESIGN: Cross-sectional.
SETTING: Two observational cohorts (CHARIOT-PRO, Alzheimer’s Disease Neuroimaging Initiative (ADNI)).
PARTICIPANTS: 830 individuals without overt clinical symptoms from CHARIOT-PRO and 812 individuals from ADNI.
MEASUREMENTS: qPCR analysis of a prioritised set of 38 miRNAs in the blood of individuals from CHARIOT-PRO, followed by a brain-specific functional enrichment analysis for the significant miRNAs. In ADNI, genetic association analysis for polymorphisms within the significant miRNAs’ genes and CSF levels of phosphorylated-tau, total-tau, amyloid-β42, soluble-TREM2 and BACE1 activity using whole genome sequencing data. Post-hoc analysis using multi-omics datasets.
RESULTS: Six miRNAs (hsa-miR-128-3p, hsa-miR-144-5p, hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-29c-3p and hsa-miR-363-3p) were downregulated in the blood of individuals with low cognitive performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The pathway enrichment analysis indicated involvement of apoptosis and inflammation, relevant in early AD stages. Polymorphisms within genes encoding for hsa-miR-29c-3p and hsa-miR-146a-5p were associated with CSF levels of amyloid-β42, soluble-TREM2 and BACE1 activity, and 21 variants were eQTL for hippocampal MIR29C expression.
CONCLUSIONS: six miRNAs may serve as potential blood biomarker of subclinical cognitive deficits in AD. Polymorphisms within these miRNAs suggest a possible interplay between the amyloid cascade and microglial activation at preclinical stages of AD.
CITATION:
A. Sadlon ; P. Takousis ; E. Evangelou ; I. Prokopenko ; P. Alexopoulos ; C.-M. Udeh-Momoh ; G. Price ; L. Middleton ; R. Perneczky ; for the Alzheimer’s Disease Neuroimaging Initiative (2023): Association of Blood MicroRNA Expression and Polymorphisms with Cognitive and Biomarker Changes in Older Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.99
ARE POPULATION-LEVEL APPROACHES TO DEMENTIA RISK REDUCTION UNDER-RESEARCHED? A RAPID REVIEW OF THE DEMENTIA PREVENTION LITERATURE
S. Walsh, L. Wallace, I. Kuhn, O. Mytton, L. Lafortune, W. Wills, N. Mukadam, C. Brayne
J Prev Alz Dis 2024;1(11):241-248
Show summaryHide summaryDementia is forecast to become increasingly prevalent, particularly in low- and middle-income countries, and is associated with high human and economic costs. Primary prevention of dementia -preventing risk factors leading to disease development - is an emerging global public health priority. Primary prevention can be achieved in two ways: individual-level or population-level. In this rapid review, we quantify the proportion of contributing interventional evidence to the dementia primary prevention literature that is concerned with either approach. We searched Medline, the National Institute for Health and Care Excellence, Cochrane, the World Health Organization, and Google to identify systematic reviews that described primary prevention interventions for dementia. We used search terms related to dementia risk reduction, intervention/policy, and review. We analysed reference lists of included dementia prevention reviews to identify contributing primary prevention evidence, and categorised these as either individual-level or population-level. Additionally, we examined search strategies to investigate the likelihood of reviews identifying available population-level interventions. We included twelve of the 527 articles retrieved. Population-level evidence was summarised by only two reviews. In these two reviews, <2.5% of the interventions described where population-level interventions. Most search strategies were weighted towards identifying individual-level evidence. Existing systematic reviews of dementia primary prevention interventions include almost no population-level evidence. Correction of this imbalance is needed to ensure that dementia prevention policies can achieve meaningful reductions in the prevalence of, and inequalities in, dementia.
CITATION:
S. Walsh ; L. Wallace ; I. Kuhn ; O. Mytton ; L. Lafortune ; W. Wills ; N. Mukadam ; C. Brayne (2023): Are Population-Level Approaches to Dementia Risk Reduction Under-Researched? A Rapid Review of the Dementia Prevention Literature. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.57
ORAL HEALTH AS A RISK FACTOR FOR ALZHEIMER DISEASE
S.M. Pruntel, B.C. van Munster, J.J. de Vries, A. Vissink, A. Visser
J Prev Alz Dis 2024;1(11):249-258
Show summaryHide summaryIn patients with Alzheimer’s disease pathophysiological changes of the brain that initiate the onset of Alzheimer’s disease include accumulation of amyloid-β plaques and phosphorylation of tau-tangles. A rather recently considered risk factor for the onset of Alzheimer’s disease is poor oral health. The aim of this systematic review of the literature was to assess the potential association(s) of oral health as a risk factor for the onset of Alzheimer’s disease. After a systematic search of Pubmed, Embase and Web of Science. A total of 1962 studies were assessed, of which 17 studies demonstrated possible associations between oral health diseases and Alzheimer’s disease. 4 theories could be distinguished that describe the possible links between oral health and the development or onset of Alzheimer’s disease; 1) role of pathogens, 2) role of inflammatory mediators, 3) role of APOE alleles and 4) role of Aβ peptide. The main common denominator of all the theories is the neuroinflammation due to poor oral health. Yet, there is insufficient evidence to prove a link due to the diversity of the designs used and the quality of the study design of the included studies. Therefore, further research is needed to find causal links between oral health and neuroinflammation that possibly can lead to the onset of Alzheimer’s disease with the future intention to prevent cognitive decline by better dental care.
CITATION:
S.M. Pruntel ; B.C. van Munster ; J.J. de Vries ; A. Vissink ; A. Visser ; (2023): Oral Health as a Risk Factor for Alzheimer Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.82
LETTER TO THE EDITOR: FIRST EXPERIENCES WITH AMYLOID-RELATED IMAGING ABNORMALITIES – YET WITHOUT IMAGING THAT CAN RULE OUT CEREBRAL INJURY OR MONITOR EFFICACY OF RECOMMENDED MANAGEMENT
P.F. Høilund-Carlsen, G. Perry, A. Alavi, J.R. Barrio
J Prev Alz Dis 2024;1(11):259-260
Show summaryHide summary
CITATION:
P.F. Høilund-Carlsen ; G. Perry ; A. Alavi ; J.R. Barrio ; (2024): Letter to the Editor: First Experiences with Amyloid-Related Imaging Abnormalities – Yet without Imaging that Can Rule Out Cerebral Injury or Monitor Efficacy of Recommended Management. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.8
REPLY TO THE LETTER TO THE EDITOR: RESPONSE TO CONCERNS RAISED ON MRI SURVEILLANCE AND CLINICAL IMPLICATIONS OF ARIA IN DISEASE MODIFYING TREATMENT
M.D. Howe, M.C. Riddle, S.P. Salloway
J Prev Alz Dis 2024;1(11):261-262
Show summaryHide summary
CITATION:
M.D. Howe ; M.C. Riddle ; S.P. Salloway ; (2024): Reply to the Letter to the Editor: Response to Concerns Raised on MRI Surveillance and Clinical Implications of ARIA in Disease Modifying Treatment. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.9
ERRATUM TO: DIGITAL CLOCK DRAWING AS AN ALZHEIMER’S DISEASE SUSCEPTIBILITY BIOMARKER: ASSOCIATIONS WITH GENETIC RISK SCORE AND APOE IN OLDER ADULTS
L.I. Thompson, M. Cummings, S. Emrani, D.J. Libon, A. Ang, C. Karjadi, R. Au, C. Liu
J Prev Alz Dis 2024;1(11):263
Show summaryHide summary
CITATION:
L.I. Thompson ; M. Cummings ; S. Emrani ; D.J. Libon ; A. Ang ; C. Karjadi ; R. Au ; C. Liu ; (2023): Erratum to: Digital Clock Drawing as an Alzheimer’s Disease Susceptibility Biomarker: Associations with Genetic Risk Score and APOE in Older Adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2023.93
ERRATUM TO: CLINICAL EFFECTS OF TRAMIPROSATE IN APOE4/4 HOMOZYGOUS PATIENTS WITH MILD ALZHEIMER’S DISEASE SUGGEST DISEASE MODIFICATION POTENTIAL
S. Abushakra, A. Porsteinsson, P. Scheltens, C. Sadowsky, B. Vellas, J. Cummings, S. Gauthier, J.A. Hey, A. Power, P. Wang, L. Shen, M. Tolar
J Prev Alz Dis 2024;1(11):264
Show summaryHide summary
CITATION:
S. Abushakra ; A. Porsteinsson ; P. Scheltens ; C. Sadowsky ; B. Vellas ; J. Cummings ; S. Gauthier ; J.A. Hey ; A. Power ; P. Wang ; L. Shen ; M. Tolar ; (2024): Erratum to: Clinical Effects of Tramiprosate in APOE4/4 Homozygous Patients with Mild Alzheimer’s Disease Suggest Disease Modification Potential. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2024.14