Ahead of print articles
EFFECT OF ACCELEROMETER-MEASURED PHYSICAL ACTIVITY ON THE ASSOCIATION BETWEEN ATRIAL FIBRILLATION AND RISK OF DEMENTIA
Le Li, Mengtong Xu, Lingmin Wu, Zhicheng Hu, Limin Liu, Likun Zhou, Minghao Zhao, Yulong Xiong, Zhenhao Zhang, Lihui Zheng, Ligang Ding, Yan Yao
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BACKGROUND: Atrial fibrillation (AF) independently increases dementia risk, but whether accelerometer-measured physical activity (PA) modifies this association remains unquantified, particularly against self-reported PA limitations.
METHODS: Prospective analysis of 91,795 UK Biobank participants with valid accelerometer data (median age 57, 42.9 % male; 2800 with baseline AF). We categorized whether measured activity met the standard recommendation [moderate-to-vigorous physical activity (MVPA) >_150 min/week]. Questionnaire-derived MVPA data from 353,643 UK Biobank participants (median age 57, male: 46.7 %) between 2006 and 2010 were used for validation. The primary outcome was the diagnosis of incident all-cause dementia. We also assessed correlation between accelerometer-derived and self-reported activity.
RESULTS: Over 7.6-year median follow-up, AF was significantly associated with a higher dementia risk [Adjusted hazard ratio (aHR): 1.76, 95 % confidential interval (CI): 1.51–2.05]. Guideline-adherent PA was associated with a lower AF-related dementia risk to non-significance (aHR: 1.36, 95 %CI: 0.96–1.91). Moreover, PA may be associated with higher protection effect on dementia risk in AF patients (aHR: 0.55, 95 % CI: 0.33–0.92) than in non-AF (aHR: 0.81, 95 % CI: 0.69–0.96), although without statistical difference (Pinteraction = 0.213). Correlation between accelerometer-derived and selfreported MVPA was weak (Spearman r = 0.155, 95 % CI: 0.148–0.162). Self-reported activity was not associated with a decreased risk of dementia in both AF and non-AF participants.
CONCLUSION: Higher accelerometer-measured PA is associated with lower AF-associated dementia risk. Future prospective studies with extended follow-up and serial activity monitoring are needed to confirm these findings.
CITATION:
Le Li ; Mengtong Xu ; Lingmin Wu ; Zhicheng Hu ; Limin Liu ; Likun Zhou ; Minghao Zhao ; Yulong Xiong ; Zhenhao Zhang ; Lihui Zheng ; Ligang Ding ; Yan Yao (2025): Effect of accelerometer-measured physical activity on the association between atrial fibrillation and risk of dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100603
LETTER TO THE EDITOR : BEYOND RECOGNITION: REFINING THE ASSESSMENT OF PUBLIC KNOWLEDGE AND RISK PERCEPTION IN DEMENTIA PREVENTION
Zhiyan Xie, Jun Su, Tao Liao
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CITATION:
Zhiyan Xie ; Jun Su ; Tao Liao (2025): Letter to the Editor: Beyond recognition: Refining the assessment of public knowledge and risk perception in dementia prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100602
CLINICAL AND BIOLOGICAL RELEVANCE OF OBJECTIVELY-DEFINED SUBTLE COGNITIVE DECLINE IN ALZHEIMER’S DISEASE: A NARRATIVE REVIEW OF NEUROIMAGING, BIOMARKER, AND CLINICAL PROGRESSION STUDIES
Amanda I. Gonzalez, Jairo E. Martinez, Averi Giudicessi, Meredith Rowe, Vivian Ku, Catarina Tristão-Pereira, Bing He, Vincent Malotaux, Yakeel T. Quiroz
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Preclinical Alzheimer’s Disease stages represent possible targets for disease-modifying intervention as well as opportunity for early identification of risk for future decline. Recent research has explored the use of objectively-defined subtle cognitive decline (Obj-SCD), an emerging classification that may identify individuals at risk for neurodegeneration before the onset of mild cognitive impairment (MCI). The Edmonds/Thomas actuarial Obj‐SCD criteria (> 1 SD below expectations, single cognitive test impaired per domain) aims to capture those who exhibit minimal cognitive difficulties that do not meet a MCI or dementia diagnosis. Given the novelty of the Obj-SCD classification, this narrative review provides an overview of neuroimaging, biomarker, and clinical progression studies to evaluate its biological and clinical significance. Using fluid-based biomarkers, neuroimaging, and longitudinal designs, studies have indicated that the Obj-SCD classification has the potential to capture AD-related pathological changes detectable before the clinical onset of MCI. In particular, recent studies indicate a unique pathological profile of Obj-SCD, differentiating it from the cognitively unimpaired and MCI stages. Studies comparing Obj-SCD and subjective cognitive complaints show that the Obj-SCD criteria may be more closely associated to early AD pathology. While the existing literature is limited, findings uphold Obj-SCD as a sensitive classification able to identify individuals at risk for future cognitive impairment. Studies on Obj-SCD indicate utility in research settings, although it faces challenges regarding its clinical implementation and effectiveness.
CITATION:
Amanda I. Gonzalez ; Jairo E. Martinez ; Averi Giudicessi ; Meredith Rowe ; Vivian Ku ; Catarina Tristão-Pereira ; Bing He ; Vincent Malotaux ; Yakeel T. Quiroz (2025): Clinical and biological relevance of objectively-defined subtle cognitive decline in Alzheimer’s disease: a narrative review of neuroimaging, biomarker, and clinical progression studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100604
BIOMARKERS IN PRECLINICAL AND EARLY ALZHEIMER’S DISEASE IN CHINA: A SCOPING REVIEW
Guoping Peng, Yan Yang, Ying Wang, Sagar Anil Chandekar, Jintai Yu
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This scoping review synthesizes evidence on fluid and neuroimaging biomarkers for preclinical and early Alzheimer’s disease (AD)—including mild cognitive impairment (MCI) and mild AD dementia—in Chinese populations, where a comprehensive overview has been lacking despite AD's increasing biomarker-based definition. We systematically searched four English databases (PubMed, EMBASE, Cochrane, and Web of Science) and three Chinese databases (CNKI, Wanfang, and CQVIP) for studies (2013–2023) reporting diagnostic accuracy of these biomarkers in Chinese preclinical and early AD (eAD) cohorts for clinical use. Due to rapid advancements in biomarker research in China, a supplementary search was conducted in the four English databases for studies published between 2024 and April 30, 2025. Of the 366 included studies investigating fluid or neuroimaging biomarkers in AD, 48 specifically evaluated biomarker performance in biomarker‑confirmed AD populations. Plasma p-tau217 showed strong performance for diagnosing MCI due to AD, and plasma p-tau217, p-tau181/Aβ42, and p-tau217/Aβ42 effectively classified amyloid-β (Aβ) pathology. Multimodal combinations and MRI-based biomarkers also performed well, though evidence is limited. In China, biomarker diagnosis of MCI due to AD is advancing rapidly, while approaches for preclinical AD, machine learning, and multi-protein panels remain in early development.
CITATION:
Guoping Peng ; Yan Yang ; Ying Wang ; Sagar Anil Chandekar ; Jintai Yu (2025): Biomarkers in preclinical and early Alzheimer’s disease in China: a scoping review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100599
NEUROPSYCHIATRIC SYMPTOMS AND DEMENTIA DEVELOPMENT: A 15-YEAR POPULATION-BASED STUDY
Francesca Remelli, Giulia Grande, Serhiy Dekhtyar, Erika J Laukka, Caterina Trevisan, Stefano Volpato, Laura Fratiglioni, Federico Triolo
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BACKGROUND: Mild Behavioral Impairment (MBI) has been proposed to detect neuropsychiatric symptoms (NPS) associated with dementia development, but evidence from population-based settings is limited.
OBJECTIVES: To (i) investigate the association between NPS in late life and the onset of dementia over 15 years in community-dwelling older adults, and (ii) test the interplay of NPS and Cognitive Impairment, No Dementia (CIND) in dementia development.
METHODS: 2597 dementia-free individuals aged 60+ from a longitudinal population-based cohort underwent cognitive assessments over 15 years. Thirty clinically-assessed NPS were mapped into five domains and, within each domain, a z-score was computed from the sum of the NPS’s points. MBI was identified when the z-score was above 1.5 standard deviations (SDs) in at least one of 5 neuropsychiatric domains. Based on a cognitive battery, CIND was defined as scoring ≥1.5 SDs below age-specific means in at least one cognitive domain. Dementia was diagnosed by DSM-IV criteria following standardized procedures.
RESULTS: MBI, present in 16.1% of the sample, was associated with a higher hazard of incident dementia over 15 years (multi-adjusted hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.31–2.17). Decreased motivation and social inappropriateness were the domains associated with incident dementia (HR 2.23, 95%CI 1.59–3.14 and HR 3.29, 95%CI 1.83–5.94, respectively). Compared to those with neither, individuals with either MBI (HR 1.37, 95%CI 1.00–1.90) or CIND (HR 2.22, 95%CI 1.73–2.84) had increased dementia incidence, especially when co-occurring (HR 4.41, 95%CI 3.04–6.39).
CONCLUSIONS: Late life NPS, especially with co-occurring cognitive impairment, was associated with a higher dementia incidence.
CITATION:
Francesca Remelli ; Giulia Grande ; Serhiy Dekhtyar ; Erika J Laukka ; Caterina Trevisan ; Stefano Volpato ; Laura Fratiglioni ; Federico Triolo (2025): Neuropsychiatric symptoms and dementia development: a 15-year population-based study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100596
CLASS-LEVEL AGGREGATION OBSCURES CLINICALLY RELEVANT HETEROGENEITY IN ANTI-AMYLOID ANTIBODY TRIALS: COMMENTS ON A COCHRANE REVIEW BY INDIVIDUAL MEMBERS OF THE EADC
Kristian Steen Frederiksen, Mercè Boada, Lutz Frölich, Milica Kramberger, Nikolaos Scarmeas, Everard Vijverberg, Pieter Jelle Visser, Gunhild Waldemar, Eric Westman, Henrik Zetterberg, Sebastiaan Engelborghs, Frank Jessen
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CITATION:
Kristian Steen Frederiksen ; Mercè Boada ; Lutz Frölich ; Milica Kramberger ; Nikolaos Scarmeas ; Everard Vijverberg ; Pieter Jelle Visser ; Gunhild Waldemar ; Eric Westman ; Henrik Zetterberg ; Sebastiaan Engelborghs ; Frank Jessen (2025): Class-level aggregation obscures clinically relevant heterogeneity in anti-amyloid antibody trials: comments on a Cochrane review by individual members of the EADC. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100598
INTERACTION OF DIET AND PHYSICAL ACTIVITY ON DEMENTIA RISK: THE ROTTERDAM STUDY
Muhammed Lamin Sambou, M. Arfan Ikram, M. Kamran Ikram, Jeremy A. Labrecque, Frank J. Wolters
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BACKGROUND: Diet and physical activity have been reported as independent risk factors for dementia, but few published studies have investigated the interactive effects of the two on dementia risk. Understanding their synergism could help shape more effective prevention strategies. Therefore, we assessed the potential interactions between MIND diet adherence and physical activity on the long-term risk of incident dementia in the population-based Rotterdam Study.
METHODS: Between 2009–2013, 5016 participants of the population-based Rotterdam Study were recruited (mean age 69.76 years, 57.9% women). All participants filled in questionnaires regarding their adherence to the MIND diet and time spent on moderate to vigorous physical activity (Metabolic Equivalent of Task [MET] hours per week). Participants were subsequently followed for incident dementia until January 1, 2021. We applied multivariable Cox regression models to assess interaction on both additive and multiplicative scales.
RESULTS: Median values were 7.5 for the MIND diet score and 28.0 for MET hours per week. Of all 5016 participants, 2718 (54.2%) adhered to a high MIND diet score (≥7.5), and 2513 (50.1%) reached at least 28.0 MET hours per week. During a mean follow-up of 6.6 years, 365 participants (7.8%) developed dementia. Both higher physical activity and higher MIND-diet score were independently associated with a lower risk of dementia, but there was no significant interaction on the additive scale (RERI [95%CI]=-0.42 [-1.26 to 0.12]), nor on the multiplicative scale (HRinteraction=0.71 [0.46–1.09]). Sex-stratified analysis suggested a negative interaction between exposures in women, but not in men.
CONCLUSION: Better adherence to the MIND-diet and higher levels of physical activity were each associated with a reduced risk of dementia, but overall there was no indication that their joint effects were greater than the product or sum of their individual parts. Potential sex differences warrant further exploration in different populations.
CITATION:
Muhammed Lamin Sambou ; M. Arfan Ikram ; M. Kamran Ikram ; Jeremy A. Labrecque ; Frank J. Wolters (2025): Interaction of diet and physical activity on dementia risk: the Rotterdam study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100594
EPIGENETIC AGING AND BLOOD BASED NEURODEGENERATION MARKERS IN LASI-DAD
Jung Ki Kim, Thalida E. Arpawong, Bharat Thyagarajan, Jennifer A. Smith, Sithara Vivek, Scott Ratliff, Sharmistha Dey, Jinkook Lee, Eileen M. Crimmins
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DNA methylation (DNAm)-based epigenetic clocks are emerging biomarkers of biological aging and have been linked to cognitive decline and dementia, but their relationship with blood-based neurodegenerative biomarkers remains understudied in low- and middle-income countries (LMIC). Using the Longitudinal Aging Study in India-Diagnostic Assessment of Dementia (LASI-DAD), we examined whether epigenetic aging was associated with levels and changes in neurodegenerative biomarkers among adults aged ≥60 years. Seven epigenetic clocks were derived from DNAm data and related to plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), phosphorylated tau 181 (pTau181), total tau, Amyloid-β (Aβ)42, Aβ40 and Aβ42/Aβ40 measured at two time points. Baseline accelerated epigenetic aging was associated with higher levels of neurodegenerative biomarkers, including pTau181, GFAP, and NfL, with more consistent associations with increases in GFAP and NfL for morbidity- and mortality-trained clocks. These findings support the utility of epigenetic clocks as scalable tools for identifying risk of neurodegeneration in LMIC settings.
CITATION:
Jung Ki Kim ; Thalida E. Arpawong ; Bharat Thyagarajan ; Jennifer A. Smith ; Sithara Vivek ; Scott Ratliff ; Sharmistha Dey ; Jinkook Lee ; Eileen M. Crimmins (2025): Epigenetic aging and blood based neurodegeneration markers in LASI-DAD. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100595
SLEEP COMPLAINTS AND GENETIC RISK OF ALZHEIMER’S DISEASE IN OLDER WOMEN: ASSOCIATIONS WITH MEMORY AND TAU DEPOSITION
Kitty K Lui, Xin Wang, Melanie A Dratva, Ella T. Lifset, Jordan Stiver, Nadine C. Heyworth, Qian Shen, Michael Thomas, Pamela N. DeYoung, Atul Malhotra, Erin E. Sundermann, Sarah J. Banks
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BACKGROUND: Emerging evidence point to a bidirectional relationship between sleep disturbances and Alzheimer’s disease (AD). Poor sleep may be an overlooked risk factor for older women, who are disproportionately affected by AD and report worse subjective sleep quality than men. High genetic AD risk—characterized by the polygenic hazard score (PHS), including apolipoprotein (APOE) ε4 carriership—may further compound the effects of disrupted sleep on AD, particularly for older women.
OBJECTIVE: This study examined the moderating effect of genetic AD risk on subjective sleep as it related to memory and tau burden in a sample of older women.
PARTICIPANTS: The sample consisted of older women (≥65 years old) from the Women Inflammation Tau Study.
MEASUREMENT: Participants completed the Pittsburgh Sleep Quality Index (PSQI), Rey Auditory Learning Test, and Brief Visuospatial Memory Test-Revised. They also underwent [18]F-MK6240 positron emission tomography. Tau burden was calculated in composite regions across Braak stages. Genetic risk groups were characterized by PHS stratified at the 75th percentile. PSQI global score × PHS group interactions on memory composite scores (N = 69) and tau burden (N = 63) were examined.
RESULTS: PSQI global score × PHS group interactions were observed on visual memory and pathological tau in Braak regions III/IV (ps<0.10). Poorer subjective sleep was associated with worse visual memory and greater limbic tau deposition only among higher genetic risk women (ps<0.04). No significant associations were observed for verbal memory or tau in Braak regions I/II or V/VI.
CONCLUSION: Older women with elevated genetic AD risk and subjective sleep difficulties may be at greater risk for visual memory deficits and tau burden in regions affected in early AD. This suggests that sleep complaints may represent a promising AD risk factor. Improving sleep may be a potential intervention target for AD mitigation and prevention, particularly for older women.
CITATION:
Kitty K Lui ; Xin Wang ; Melanie A Dratva ; Ella T. Lifset ; Jordan Stiver ; Nadine C. Heyworth ; Qian Shen ; Michael Thomas ; Pamela N. DeYoung ; Atul Malhotra ; Erin E. Sundermann ; Sarah J. Banks (2025): Sleep complaints and genetic risk of Alzheimer’s disease in older women: associations with memory and tau deposition. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2025.8
DEPRESSIVE SYMPTOMS AS A RISK FACTOR OR PRODROME OF DEMENTIA: MULTI-STATE COGNITIVE TRANSITIONS MODIFIED BY AGE AND POLYGENIC RISK
Ziyang Ren, Ruyi Zhang, Shuai Guo, Yihao Zhao, Jufen Liu, Xiaoying Zheng
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BACKGROUND: Whether depressive symptoms signal a risk factor or a prodromal symptom of dementia, and how this depends on age, genetic susceptibility, and cognitive stages, remains controversial.
OBJECTIVES: To examine the association between depressive symptoms and incident dementia and cognitive transitions, and to test effect modification by age and AD genetic susceptibility (APOE and AD polygenic risk score [PRS]).
DESIGN: Longitudinal cohort study (1998–2020) using repeated assessments; incident dementia was modeled using Fine-Gray competing-risk models, and cognitive transitions were modeled with multi-state Markov models.
SETTING: The U.S. Health and Retirement Study.
PARTICIPANTS: For the main incident dementia analysis, 13,225 dementia-free participants were included at baseline; genetic and repeated-measures analyses were restricted to 12,089 participants with complete PRS/APOE data.
MEASUREMENTS: Depressive symptoms were assessed with the 8-item CES-D. Cognitive status was classified as normal cognition, subjective memory complaint (SMC), cognitive impairment no dementia (CIND), or dementia. AD genetic susceptibility was indexed by APOE and AD PRS. Outcomes included incident dementia and transitions across cognitive states.
RESULTS: Baseline depressive symptoms (prevalence 11.3%) were associated with a higher incidence of dementia (sHR 1.24, 95% CI 1.10–1.39), with stronger associations in late midlife (50–59y: sHR 1.65) than ≥60y (sHR 1.19; P for interaction=0.001). After excluding dementia occurring within 5–10y, the associations for late midlife (but not ≥60y) remained significant (sHR for 5y=1.57; for 10y=1.55, both P for interaction≤0.030). AD PRS modified this association: depressive symptoms predicted dementia only among individuals with lower AD PRS, whereas APOE ε4 showed no modification. Multi-state analyses showed depressive symptoms accelerated progression across the cognitive continuum (e.g., normal cognition → SMC, HR=1.49; SMC → CIND, HR=1.33; CIND → dementia, HR=1.17) and reduced reversion to normal cognition. Furthermore, AD genetic susceptibility was positively associated with depressive symptom burden, specifically at the SMC stage.
CONCLUSIONS: Depressive symptoms in late midlife, especially with lower AD PRS, are more consistent with a potentially modifiable risk marker for dementia, whereas depressive symptoms emerging at SMC in genetically susceptible adults may more often reflect prodromal disease activity.
CITATION:
Ziyang Ren ; Ruyi Zhang ; Shuai Guo ; Yihao Zhao ; Jufen Liu ; Xiaoying Zheng (2025): Depressive symptoms as a risk factor or prodrome of dementia: multi-state cognitive transitions modified by age and polygenic risk. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100577
LETTER TO THE EDITORE: CLARITY AD OPEN-LABEL EXTENSION DATA DO NOT ROBUSTLY CONFIRM DISEASE COURSE MODIFICATION BY LECANEMAB IN APOE4 HETEROZYGOTES AND NON-CARRIERS
Lutz Froelich
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CITATION:
Lutz Froelich (2025): Letter to the editor: Clarity AD open-label extension data do not robustly confirm disease course modification by lecanemab in ApoE4 heterozygotes and non-carriers. # TJPAD-D-26-00165. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100588
RNA-BASED THERAPEUTICS FOR ALZHEIMER’S DISEASE AND RELATED TAUOPATHIES: CHALLENGES AND OPPORTUNITIES
Binita Rajbanshi, Ilaria Brentari, Michela Alessandra Denti, Jeffrey L. Cummings, Anuj Guruacharya
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Tauopathies are neurodegenerative diseases characterized by pathological tau protein accumulation. Though therapies involving monoclonal antibodies and small-molecule inhibitors have progressed, they have so far failed in multiple clinical trials, underscoring the need for innovative molecular approaches. RNA-based therapies offer an alternative disease-modifying approach by being able to target tau at its molecular origin. Diverse modalities, such as mRNA, ASO, RNAi, and SSO, offer distinct promises. Though their challenges are equally diverse, they also share common problems. This review examines the nascent field of RNA therapeutics for tauopathies, outlining emerging modalities, translational barriers, molecular targets, clinical trials, and patent trends.
CITATION:
Binita Rajbanshi ; Ilaria Brentari ; Michela Alessandra Denti ; Jeffrey L. Cummings ; Anuj Guruacharya (2025): RNA-based therapeutics for Alzheimer’s disease and related tauopathies: challenges and opportunities. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100585
TOP FIVE ALZHEIMER DISEASE TRIAL ELIGIBILITY CRITERIA FAVOR MEN COMPARED TO WOMEN IN A CLINIC-BASED COHORT
Lieza G. Exalto, Siti S. Syaziyah, Xiaotian T Fang, Niels D. Prins, Sietske A.M. Sikkes, Wiesje M. van der Flier, Everard G.B. Vijverberg, Yvonne M.F. Lim
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BACKGROUND: Less women participate in Alzheimer Disease (AD) trials compared to their estimated representation in the global dementia population.
OBJECTIVES: We aimed to apply five most commonly used eligibility criteria to a real-world memory clinic population to compare male and female eligibility according to these criteria.
DESIGN: Observational.
SETTING: Memory clinic setting.
PARTICIPANTS: Consecutive patients (2000–2024) from Amsterdam Dementia Cohort with a diagnosis of mild cognitive impairment (MCI) or AD (n = 3835).
MEASUREMENTS: Free-text eligibility criteria of n = 608 phase II and III AD drug trials were downloaded from ClinicalTrials.gov (March 28, 2025). A machine-learning model was trained and validated to extract all eligibility criteria. Next the criteria were applied on observational real world data from on memory clinic diagnostic work-up.
RESULTS: Top 5 most common AD clinical trial eligibility criteria were 1) no other central nervous system disorder related to cognitive impairment (84%), 2) participation of a caregiver (72%), 3) MMSE (66%, range 20–30), 4) no comorbidities, specifically vascular and mental health (62%), 5) no contra-indications for study procedures such as lumbar puncture, MRI and PET (59%). Applying the abovementioned criteria results in 33% of men and 23% of women remaining eligible (p<.001). Main reason for non-eligibility is caretaker absence (applicable for 20% of men and 38% of women) and low MMSE (32% of man and 54% of women).
CONCLISION: Based on five commonly used eligibility criteria of AD clinical trials, women in our clinic-based cohort are less eligible for participation in AD drug trials than men. This discrepancy was mainly attributed to lack of caregiver presence and lower MMSE at presentation. These results provide clues for trial design to facilitate more equal inclusion of women.
CITATION:
Lieza G. Exalto ; Siti S. Syaziyah ; Xiaotian T Fang ; Niels D. Prins ; Sietske A.M. Sikkes ; Wiesje M. van der Flier ; Everard G.B. Vijverberg ; Yvonne M.F. Lim (2025): Top five Alzheimer Disease trial eligibility criteria favor men compared to women in a clinic-based cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100580
VIRTUAL REALITY-BASED TRAINING IN PATIENTS WITH ALZHEIMER\'S DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS
Junjie Wang, Can Wu, Kedong Zhu, Xiaoshan Qi, Guiqin Chen
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BACKGROUND AND OBJECTIVES: Prior meta-analyses have suggested that training utilizing virtual reality (VR) serves as a secure and effective intervention for elderly individuals experiencing mild cognitive impairment (MCI). Nevertheless, the effectiveness of such interventions appears to differ among various populations and cognitive domains. Furthermore, there remains a significant gap in understanding the effectiveness of VR-based training, specifically among individuals diagnosed with Alzheimer's disease (AD).
METHODS: The researchers conducted a comprehensive search of databases, including Web of Science, PubMed, Cochrane Library, and EMBASE up until July 1, 2025, focusing on randomized controlled trials that investigated VR-based training in patients diagnosed with AD. The outcomes measured were categorized and analyzed separately, encompassing overall cognitive performance, distinct cognitive domains, psychosocial function, physical capabilities, and the execution of daily living activities within the context of AD trials.
RESULTS: Of the 265 publications identified, 11 (4.15%) randomized controlled trials (RCTs) eventually met all eligibility criteria. Those who received VR-based training showed significantly better global cognitive function [SMD (95%CI) = 0.44 (0.21–0.68)] and Short-term memory [SMD (95%CI) = 0.62 (0.25–0.99)] than the controls. However, no significant improvements were observed in areas such as executive function, spatial memory, activities of daily living, quality of life, balance and coordination, fear of falling, risk of falls, and depression levels.
CONCLUSION: VR-based interventions demonstrated beneficial effects on global cognitive function and short-term memory in AD populations. Due to the small sample size, the current research on evidence for efficacy in people with AD is weak and limited in many indicators.
CITATION:
Junjie Wang ; Can Wu ; Kedong Zhu ; Xiaoshan Qi ; Guiqin Chen (2025): Virtual reality-based training in patients with alzheimer's disease: A systematic review and meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100590
ADAPTING THE SPANISH HEALTHCARE SYSTEM FOR DISEASE-MODIFYING TREATMENTS IN EARLY-STAGE ALZHEIMER’S DISEASE
R. Sánchez Valle, A. Lleó Bisa, A. Villarejo Galende, E. Cuartero Rodríguez, J. Escudero-Torrella, N. Bargallo Alabart
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BACKGROUND: The emergence of disease-modifying therapies targeting amyloid pathology represents a major paradigm shift in the management of Alzheimer disease (AD). However, their implementation poses substantial organizational, infrastructural, and clinical challenges for health systems.
OBJECTIVES: To identify the key challenges and establish priority recommendations for the effective incorporation of amyloid-targeting therapies into the Spanish National Health System.
DESIGN, SETTING, AND PARTICIPANTS: This multiphase consensus study was conducted within the Spanish National Health System between September 2024 and July 2025. The study comprised a narrative literature review, qualitative research, regional workshops, and a modified RAND/UCLA Delphi process. A total of 56 experts participated, including a scientific committee of 6 Alzheimer disease specialists and an expert panel of 50 multidisciplinary professionals involved in AD care.
MEASUREMENTS: Identification of key challenges across the AD care pathway; development, evaluation, and prioritization of consensus-based recommendations; and estimation of patient demand, including projected increases in day hospital activity and magnetic resonance imaging utilization.
RESULTS: Ten key challenge areas were identified, encompassing early detection and referral, diagnostic confirmation, assessment of patient eligibility, treatment administration in day hospitals, monitoring of amyloid-related imaging abnormalities, evaluation of treatment effectiveness, infrastructure and capacity, professional training, patient information and support, and health care planning. Of the 43 recommendations assessed, 38 were rated as appropriate and necessary, with 14 prioritized for immediate implementation. Demand estimation models indicated that 11 to 26 patients per 100,000 inhabitants could be treated under current care patterns, increasing to 17 to 115 per 100,000 inhabitants under alternative eligibility scenarios.
CONCLUSIONS: This consensus defines the clinical, organizational, and infrastructural requirements necessary to integrate amyloid-targeting therapies into routine care within the Spanish National Health System. The prioritized recommendations define immediate actions to address the challenges identified and may serve as a reference for other health systems facing similar implementation processes.
CITATION:
R. Sánchez Valle ; A. Lleó Bisa ; A. Villarejo Galende ; E. Cuartero Rodríguez ; J. Escudero-Torrella ; N. Bargallo Alabart (2025): Adapting the spanish healthcare system for disease-modifying treatments in early-stage alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100586
PHENOTYPING OF MILD BEHAVIORAL IMPAIRMENT DOMAINS IN MULTI-REGIONAL DEMENTIA-FREE OLDER ADULTS OF CHINESE ETHNICITY: IMPULSE DYSCONTROL AS THE LEADING DOMAIN
Yingqi Liao, Yaping Zhang, Haoran Zhang, Yan Li, Dylan X. Guan, Yifan Yan, Yuek Ling Chai, Mitchell K.P. Lai, Shifu Xiao, Christopher L.H. Chen, Xin Xu
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BACKGROUND: Mild behavioral impairment (MBI) is an early neurobehavioral marker of dementia, yet MBI domain patterns remain underexplored among populations of Chinese ethnicity. This study aimed to characterize MBI domain phenotypes by examining the prevalence of MBI domains and identifying the leading domain across multi-regional cohorts of dementia-free older adults of Chinese ethnicity.
METHODS: Data from three previously unpublished datasets (Hangzhou community cohort, China Longitudinal Aging Study and Singapore memory clinic cohort) and three published studies were integrated to estimate the MBI domain prevalence, measured by the Neuropsychiatric Inventory (NPI) and/or MBI-Checklist (MBI-C), through a random-effects meta-analysis. Within the Hangzhou cohort, cross-instrument consistency was evaluated. Exploratory analyses were performed in the Singapore cohort on associations between MBI domains and incident dementia.
RESULTS: Among 1817 participants, impulse dyscontrol was the most prevalent MBI domain, followed by affective dysregulation and decreased motivation, consistently across instruments and cognitive status. In the exploratory longitudinal analyses, impulse dyscontrol was associated with a greater likelihood of incident dementia (HR = 5.05, 95%CI = 2.92 – 8.73).
CONCLUSIONS: Impulse dyscontrol was the leading MBI domain among older adults of Chinese ethnicity, with potential clinical relevance for early identification and dementia risk stratification.
CITATION:
Yingqi Liao ; Yaping Zhang ; Haoran Zhang ; Yan Li ; Dylan X. Guan ; Yifan Yan ; Yuek Ling Chai ; Mitchell K.P. Lai ; Shifu Xiao ; Christopher L.H. Chen ; Xin Xu (2025): Phenotyping of mild behavioral impairment domains in multi-regional dementia-free older adults of Chinese ethnicity: impulse dyscontrol as the leading domain. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100589
LETTER TO THE EDITOR: CLARITY AD OPEN-LABEL EXTENSION DATA DO NOT ROBUSTLY CONFIRM DISEASE COURSE MODIFICATION BY LECANEMAB IN APOE4 HETEROZYGOTES AND NON-CARRIERS
Jemma Hazan, Kathy Y. Liu, Robert Howard
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CITATION:
Jemma Hazan ; Kathy Y. Liu ; Robert Howard (2025): Letter to the Editor: Clarity AD open-label extension data do not robustly confirm disease course modification by lecanemab in ApoE4 heterozygotes and non-carriers. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100587
EDITORIAL : BEYOND AMYLOID POSITIVITY: BIOLOGICAL HETEROGENEITY IN THE REAL-WORLD USE OF LECANEMAB
Michael S. Rafii
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CITATION:
Michael S. Rafii (2025): Editorial: Beyond amyloid positivity: Biological heterogeneity in the real-world use of lecanemab. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100584
INCOME, DIET, AND COGNITIVE FUNCTION: OBSERVATIONAL ANALYSES AND CANDIDATE METABOLOMIC PATHWAYS IDENTIFIED BY MENDELIAN RANDOMIZATION
Xingguang Zhao, Weijian Wu, Qiaoxuan Zhang, Mengqian Ouyang, Haoyu Luo, Qun Yu, Yingren Mai, Zhiyu Cao, Shaoqing Yang, Mingsong Xu, Jun Liu, Wang Liao
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BACKGROUND: Household income has been shown to have impact on cognitive function, with dietary patterns and gut microbiota–related metabolic pathways potentially acting as mediating pathways. Our study integrates observational analyses and Mendelian randomization (MR) to explore these associations.
METHODS: The observational analysis included 13,457 participants from the UK Biobank who experienced cognitive transitions. A multistate Markov model was applied to assess the effect of income level on cognitive trajectory, while mediation analysis and quantile regression were performed using baseline data. We applied a two-sample, two-step MR approach utilizing genetic instruments from the IEU Open genome-wide association studies (GWAS) project to determine the causal effects of income on cognition, and further estimate the mediating roles of dietary patterns and 1400 gut metabolites linking income with cognitive performance.
RESULTS: Over a median follow-up of 8.96 years, a total of 14,040 cognitive transitions were recorded (7429 deterioration events and 6801 improvements), with higher income associated with a lower risk of cognitive deterioration. MR analyses confirmed a causal relationship between income and cognitive performance (OR: 2.140, 95% CI: 1.923–2.381; P < 0.001). Notably, cheese and coffee intake demonstrated significant mediation effects in both observational and two-way, two-step MR. The protective effect of cheese appeared to be mediated by gut metabolites, particularly via tryptophan/tyrosine and carnitine/ergothioneine.
CONCLUSIONS: Our findings indicate a significant link between income and cognitive performance, cheese and dried fruit may mediate this protective effect through amino acid and carnitine metabolism pathways. Interventions targeting dietary patterns have the potential to prevent cognitive decline attributable to low income.
CITATION:
Xingguang Zhao ; Weijian Wu ; Qiaoxuan Zhang ; Mengqian Ouyang ; Haoyu Luo ; Qun Yu ; Yingren Mai ; Zhiyu Cao ; Shaoqing Yang ; Mingsong Xu ; Jun Liu ; Wang Liao (2025): Income, diet, and cognitive function: observational analyses and candidate metabolomic pathways identified by Mendelian randomization. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100582
TETANUS, DIPHTHERIA AND PERTUSSIS VACCINATION AND RISK FOR INCIDENT DEMENTIA AMONG ADULTS WITH DOWN SYNDROME
Kimberly Schiel, Joanne Salas, Anjani Urban, Daniel F. Hoft, Jeffrey F. Scherrer
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BACKGROUND: Adult vaccination is inversely associated with incident Alzheimer’s Disease and Related Dementias.
OBJECTIVES: We determined if Tetanus, Diphtheria and Pertussis (Tdap) vaccination was linked to incident Alzheimer’s Disease and dementia among adults with Down Syndrome, 50% of whom develop Alzheimer’s Disease by age 60.
DESIGN: This is a retrospective cohort study using TriNetX nationally distributed electronic health records from 2013 to 2024.
SETTING: Historical medical record data.
PARTICIPANTS: 5591 patients with Down Syndrome across the United States. Eligible patients were free of Alzheimer’s Disease and dementia prior to index. Index date could occur 1/1/2015 to 1/1/2020 allowing for 5 to 10 years of possible follow-up time.
MEASUREMENTS: Vaccination was measured using product name and procedure codes and Alzheimer’s Disease and dementias was defined by ICD-10 codes.
RESULTS: The mean age of the cohort was 50.0 (±8.3), 50.1% were female and 72.1% were White. After controlling for confounding, Tdap vaccination vs. remaining without Tdap vaccination was associated with lower Alzheimer’s Disease and dementia risk (HR=0.74; 95%CI:0.57–0.98).
CONCLUSIONS: In a cohort of patients with Down Syndrome, Tdap vaccination was associated with a 26% lower risk for Alzheimer’s Disease and dementia. This is a novel and important finding because existing studies of vaccination and reduced risk for Alzheimer’s Disease and dementia have been among cognitively intact adults. This study reveals benefits of vaccination even among those at high risk for Alzheimer’s Disease and dementia due to Down Syndrome. Future studies are needed to understand the mechanisms underlying this relationship.
CITATION:
Kimberly Schiel ; Joanne Salas ; Anjani Urban ; Daniel F. Hoft ; Jeffrey F. Scherrer (2025): Tetanus, diphtheria and pertussis vaccination and risk for incident dementia among adults with down syndrome. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100583
LETTER TO THE EDITOR: HEALTH-ECONOMIC CHALLENGES FOR NEW ALZHEIMER’S DISEASE TREATMENTS
Jinjing Fu, Anders Sköldunger, Angela Bradshaw, Hana Marie Broulíková, Chiara C Brück, Jack M. Chapel, Sabine Grimm, Anna Hansson, William L. Herring, Jakub Hlávka, Men Thi Hoang, Linus Jönsson, Filipa Landeiro, Javier Mar, Alison McKean, Matej Misik, Peter Neumann, Thomas Rapp, Craig Ritchie, Anja Schiel, Yi Sun, Dominic Trépel, David Trueman, P.J. van der Veere, Lynn van Rosmalen, Jean L Vonsy, Lizzie Walker, Anders Wimo, Bengt Winblad, Xin Xia, Ron Handels
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CITATION:
Jinjing Fu ; Anders Sköldunger ; Angela Bradshaw ; Hana Marie Broulíková ; Chiara C Brück ; Jack M. Chapel ; Sabine Grimm ; Anna Hansson ; William L. Herring ; Jakub Hlávka ; Men Thi Hoang ; Linus Jönsson ; Filipa Landeiro ; Javier Mar ; Alison McKean ; Matej Misik ; Peter Neumann ; Thomas Rapp ; Craig Ritchie ; Anja Schiel ; Yi Sun ; Dominic Trépel ; David Trueman ; P.J. van der Veere ; Lynn van Rosmalen ; Jean L Vonsy ; Lizzie Walker ; Anders Wimo ; Bengt Winblad ; Xin Xia ; Ron Handels (2025): Letter to the Editor: Health-economic challenges for new Alzheimer’s disease treatments. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100575
ASSOCIATIONS OF PLASMA BIOMARKERS WITH AGE IN THE PRESENILIN-1 E280A AUTOSOMAL DOMINANT ALZHEIMER\'S DISEASE KINDRED
Vincent Malotaux, Vivian Ku, Paula Ospina Lopera, Yi Su, Yinghua Chen, Alpana Singh, Jonathan Ruiz-Triviño, María José Hidalgo, Laura Osorio, Laura Serna, Daniela Giraldo, Diana Alzate, Bing He, Catarina Tristão-Pereira, Liliana Ramirez Gomez, Sonia Do Carmo, A. Claudio Cuello, Nicholas J. Ashton, Eric M. Reiman, David Aguillón, Yakeel T. Quiroz
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BACKGROUND: Autosomal-dominant Alzheimer’s disease (ADAD) offers a model to define early biological changes in Alzheimer’s disease due to its predictable age at symptom onset. Although ultrasensitive plasma assays are available, their associations with age in ADAD remain incompletely characterized.
OBJECTIVES: To characterize age-related changes in plasma biomarkers and examine associations with cognition in PSEN1 E280A ADAD.
DESIGN AND SETTING: Cross-sectional observational study in members of the Colombian PSEN1 E280A kindred.
PARTICIPANTS: A total of 164 individuals were included, comprising 83 mutation carriers (mean age 34.36±9.82 years; 54% female) and 81 non-carriers (mean age 33.75±9.84 years; 52% female).
MEASUREMENTS: Plasma Aβ42/Aβ40, phospho-tau217 (p-tau217), brain-derived tau (BD-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were quantified. Sex-adjusted associations with age, divergence ages between groups, classification performance (ROC curves), and associations with cognition (MMSE and CERAD delayed recall) were assessed.
RESULT: All plasma biomarkers were associated with age (p < .01). Divergence between carriers and non-carriers began with Aβ42/Aβ40 before age 18, followed by p-tau217 (26.0 years), GFAP (26.1 years), BD-tau (27.9 years), and NfL (38.7 years). Aβ42/Aβ40 showed the highest discrimination of mutation status (AUC=0.99), followed by p-tau217 (AUC=0.87) and GFAP (AUC=0.84). Among carriers, p-tau217, GFAP, BD-tau, and NfL were associated with MMSE, while p-tau217, GFAP, and NfL predicted CERAD delayed recall.
CONCLUSION: Plasma biomarkers exhibit a temporal cascade in PSEN1 E280A ADAD. P-tau217 and GFAP show the strongest associations with early cognitive decline, suggesting their potential utility for tracking disease progression and monitoring treatment effects in E280A carriers.
CITATION:
Vincent Malotaux ; Vivian Ku ; Paula Ospina Lopera ; Yi Su ; Yinghua Chen ; Alpana Singh ; Jonathan Ruiz-Triviño ; María José Hidalgo ; Laura Osorio ; Laura Serna ; Daniela Giraldo ; Diana Alzate ; Bing He ; Catarina Tristão-Pereira ; Liliana Ramirez Gomez ; Sonia Do Carmo ; A. Claudio Cuello ; Nicholas J. Ashton ; Eric M. Reiman ; David Aguillón ; Yakeel T. Quiroz (2025): Associations of plasma biomarkers with age in the presenilin-1 E280A autosomal dominant Alzheimer's disease kindred. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100578
AMYLOID PATHOLOGY AND MODIFIABLE RISK FACTORS IN COGNITIVE DECLINE AMONG COGNITIVELY UNIMPAIRED OLDER ADULTS
Ying-Hsin Hsu, Chih-Kuang Liang, Ming-Yueh Chou, Jaysón Davidson, Yu-Chun Wang, Mike A. Nalls, Luigi Ferrucci, Mark Cookson, Hirotaka Iwaki
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BACKGROUND: Alzheimer’s disease (AD) pathology, particularly amyloid-β (Aβ) deposition, occurs years before clinical symptoms. Modifiable risk factors may influence cognitive trajectories during this preclinical stage, but whether amyloid status alters their effects remains unclear.
OBJECTIVES: To investigate interactions between amyloid pathology and modifiable risk factors in predicting longitudinal cognitive decline among cognitively unimpaired older adults.
DESIGN AND SETTING: This study was a secondary analysis of data derived from two large multicenter longitudinal cohort studies, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study.
PARTICIPANTS: A total of 1707 cognitively unimpaired adults aged 65–85 years were included, comprising 1169 amyloid-positive participants from the A4 Study (Aβ+) and 538 amyloid-negative participants from the LEARN Study (Aβ–).
MEASUREMENTS: Cognitive function was assessed every six months using the Preclinical Alzheimer’s Cognitive Composite (PACC) over a mean follow-up of 4.9 years. Eight established modifiable risk factors—low education, alcohol use, diabetes, high cholesterol, high blood pressure, obesity, depressive symptoms, and physical inactivity—were evaluated. Linear mixed-effects models were applied to examine associations between each risk factor and longitudinal PACC decline, and to test interactions with amyloid status, adjusting for demographic and genetic covariates.
RESULTS: Significant interactions between amyloid status and modifiable risk factors were observed for diabetes (adjusted β = −0.206, p = 0.032), high cholesterol (adjusted β = −0.155, p < 0.001), and physical inactivity (adjusted β = −0.161, p = 0.046), indicating combined effects rather than additive effects on cognitive decline among Aβ+ individuals. In the A4 study (Aβ+), low education, diabetes, high cholesterol, and physical inactivity were independently associated with accelerated cognitive decline, whereas obesity was linked to slower decline. In contrast, in the LEARN study (Aβ-), these associations were not statistically significant.
CONCLUSIONS: In conclusion, the significant interactions with amyloid status were observed for diabetes, high cholesterol, and physical inactivity, indicating that these risk factors were associated with faster cognitive decline specifically in Aβ+ individuals. The results suggest that consideration of amyloid status may be important when evaluating the potential role of metabolic and lifestyle risk factors in preclinical cognitive decline. In Aβ+ individuals, obesity was associated with slower cognitive decline, while low education was linked to lower baseline cognition or a reduced symptom threshold, without a significant interaction with amyloid status. Future studies should incorporate amyloid status and longitudinal biomarkers to assess whether modifying these factors can slow preclinical cognitive decline.
CITATION:
Ying-Hsin Hsu ; Chih-Kuang Liang ; Ming-Yueh Chou ; Jaysón Davidson ; Yu-Chun Wang ; Mike A. Nalls ; Luigi Ferrucci ; Mark Cookson ; Hirotaka Iwaki (2025): Amyloid pathology and modifiable risk factors in cognitive decline among cognitively unimpaired older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100574
EDITORIAL : LIPID-LOWERING REGIMENS IN ALZHEIMER’S DISEASE DEMENTIA: SMALL EFFECTS WITH POTENTIAL LONG-TERM BENEFIT
Tobias Hartmann
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CITATION:
Tobias Hartmann (2025): Editorial: Lipid-lowering regimens in Alzheimer’s disease dementia: small effects with potential long-term benefit. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100576
SPEECH-BASED DIGITAL BIOMARKERS FOR EARLY ETIOLOGICAL STRATIFICATION OF ALZHEIMER’S DISEASE AND FRONTOTEMPORAL DEGENERATION: A BIOMARKER-CONFIRMED PROSPECTIVE STUDY
Eloïse Da Cunha, Valeria Manera, Frédéric Chorin, Justine Lemaire, Alexandra Plonka, Aurélie Mouton, Raphaël Zory, Auriane Gros
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BACKGROUND: Early differentiation between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) is a prerequisite for secondary prevention and targeted trial enrollment, yet remains challenging at disease onset. We investigated whether automated speech analysis could serve as a digital biomarker for early etiological stratification across clinically heterogeneous presentations.
METHODS: In this prospective biomarker-confirmed prognostic study, 172 participants (108 patients with biomarker-confirmed AD or FTLD and 64 controls) completed a standardized speech protocol at initial clinical assessment. Acoustic, temporal, and phonatory features were automatically extracted. Machine learning models and a stacking ensemble were trained using stratified, repeated 5-fold cross-validation to discriminate between AD and FTLD pathology, with exploratory analysis extending to atypical and rare phenotypes crossed with physiopathology, including primary progressive aphasia (PPA) variants.
RESULTS: Speech-based models achieved high sensitivity and specificity in distinguishing physiopathology independently (mean area under the curve (AUC)=0.986) and crossed phenotype and physiopathological diagnostic association (mean AUC=0.966).The ensemble identified 82% of cases with clinicopathological discordance. Interpretability analyses revealed distinct speech signatures: AD was associated with global speech slowing and phonatory instability, while FTLD was characterized by reduced verbal output and acoustic hypo-expressivity.
CONCLUSIONS: Automated speech analysis provides a promising non-invasive digital biomarker for the early etiological stratification of AD and FTLD, including atypical phenotypes, with high accuracy in a monocentric biomarker-confirmed cohort. These findings support the feasibility of speech-based etiological stratification and its potential to complement existing biomarker frameworks, particularly in cases of clinicopathological discordance. External validation is required before clinical deployment can be considered.
CITATION:
Eloïse Da Cunha ; Valeria Manera ; Frédéric Chorin ; Justine Lemaire ; Alexandra Plonka ; Aurélie Mouton ; Raphaël Zory ; Auriane Gros (2025): Speech-based digital biomarkers for early etiological stratification of Alzheimer’s disease and frontotemporal degeneration: a biomarker-confirmed prospective study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100573
THE ASSOCIATION BETWEEN OMEGA-3 SUPPLEMENTATION AND COGNITIVE DECLINE IN OLDER ADULTS
Zheng-Bin Liao, Zi-Cheng Hu, Gui-Hua Zeng, Jia Chen, Xin-Peng Li, Yu-Hui Liu, Xiu-Qing Yao, Ye-Ran Wang, Alzheimer’s Disease Neuroimaging Initiative
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BACKGROUND: While omega-3 fatty acid supplementation is widely used for cognitive protection, its efficacy remains controversial, and its impact on core Alzheimer's disease (AD) pathologies in humans is not well-established.
METHODS: This longitudinal study utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We employed linear mixed-effects models to assess the association between omega-3 supplementation and longitudinal cognitive decline, and mediation analyses to examine whether this relationship was mediated by core AD pathologies (Aβ-PET, tau-PET, T1-MRI, FDG-PET).
RESULTS: Omega-3 supplementation was associated with significantly accelerated cognitive decline, as evidenced by a faster decrease in MMSE scores (β = -0.266, p < 0.001) and a faster increase in both ADAS-Cog13 (β = 0.823, p < 0.001) and CDR-SB scores (β = 0.205, p < 0.001). This association was not mediated by Aβ deposition, tau pathology, or gray matter atrophy. Instead, longitudinal FDG hypometabolism within AD-vulnerable regions served as a significant mediating pathway, accounting for 30.8%, 40.8%, and 19.0% of the total effect on the decline in MMSE, ADAS-Cog13, and CDR-SB, respectively.
CONCLUSIONS: Omega-3 supplementation may be associated with accelerated cognitive decline in older adults, potentially through adverse effects on cerebral synaptic function rather than classical AD proteinopathies. These findings challenge the prevailing view of omega-3 as uniformly beneficial and highlight the need for a cautious reassessment of its widespread use for cognitive protection.
CITATION:
Zheng-Bin Liao ; Zi-Cheng Hu ; Gui-Hua Zeng ; Jia Chen ; Xin-Peng Li ; Yu-Hui Liu ; Xiu-Qing Yao ; Ye-Ran Wang ; Alzheimer’s Disease Neuroimaging Initiative (2025): The association between omega-3 supplementation and cognitive decline in older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100569
THE CONCURRENT BURDEN OF ALZHEIMER’S PATHOLOGY, CEREBRAL AMYLOID ANGIOPATHY, AND MICROINFARCTS ON COGNITIVE DECLINE
Mingyao You, Chao Tang, Lianfei Liu, Dengpeng Chen, Yillin Wu, Dian He
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BACKGROUND: Alzheimer’s disease (AD) is frequently complicated by vascular co-morbidities. However, the specific mechanistic pathways by which vascular lesions interact with genetic susceptibility to accelerate cognitive decline remain unclear. This study investigated whether cerebral amyloid angiopathy (CAA) and cortical microinfarcts mediate the impact of AD pathology on cognition and evaluated the modifying role of APOE genotype.
METHODS: We conducted a retrospective clinico-pathological study using the National Alzheimer’s Coordinating Center (NACC) database. The cohort included autopsy-confirmed participants aged 50 and older. Structural Equation Modeling (SEM) was employed to quantify the pathways linking AD pathology (Thal phase) to CAA severity, microinfarcts, and cognitive performance (CDR-Sum of Boxes). We further assessed the cumulative burden of pathology by comparing "Pure AD" cases against those with a "Triple Hit" of AD, CAA, and microvascular injury.
RESULTS: SEM analysis identified a significant statistical mediation pathway wherein parenchymal amyloid is strongly associated with CAA, which correlates with an increased risk of microinfarcts and subsequent cognitive dysfunction. We observed a significant gene-pathology interaction: APOE ε4 carriers demonstrated a steeper trajectory of cognitive decline for a given severity of CAA compared to non-carriers. Furthermore, the "Triple Hit" group exhibited significantly worse cognitive impairment than the "Pure AD" group (P < 0.001), independent of age and education.
CONCLUSIONS: Vascular pathology is a critical mediator of cognitive failure in AD, particularly in APOE ε4 carriers. The concurrent "Triple Hit" of proteinopathy and vasculopathy is associated with a profound failure of cognitive reserve, likely reflecting a more advanced global disease state. These findings highlight the urgent need to target vascular resilience as a disease-modifying strategy in Alzheimer’s disease.
CITATION:
Mingyao You ; Chao Tang ; Lianfei Liu ; Dengpeng Chen ; Yillin Wu ; Dian He (2025): The concurrent burden of Alzheimer’s pathology, cerebral amyloid angiopathy, and microinfarcts on cognitive decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100568
COST ANALYSES OF PLASMA P-TAU217 VERSUS P-TAU217/AΒ42 RATIO USING TWO-STEP APPROACH IN THE JAPANESE HEALTH CARE SYSTEM
Masanori Kurihara, Ryoko Ihara, Kenichiro Sato, Atsushi Iwata
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Plasma p-tau217 may offer a cost-saving effect in diagnosing Alzheimer’s disease. However, each healthcare system has different costs, and its impact on evaluating anti-amyloid β (Aβ) therapies in Japan remains unclear. We conducted cost analyses using a two-step approach with a recently released application, assuming that measuring two analytes (p-tau217/Aβ42) would reduce the intermediate zone to 7%, despite doubling the price. Plasma biomarker costs were simulated from 100 to 800 USD. Cost savings ranged 34–79% compared with positron electron tomography (PET) and -5.6%–74% compared with in-patient cerebrospinal fluid (CSF) Aβ42/40 when 14.7% were in the intermediate zone. Savings were comparably high by measuring two analytes at 100 or 200 USD per analyte and gradually differed (one analyte better savings than two) as the cost per analyte increased. Both plasma p-tau217 and p-tau217/Aβ42 showed substantial cost-saving effects, with comparably high savings at lower costs (100, 200 USD) per analyte.
CITATION:
Masanori Kurihara ; Ryoko Ihara ; Kenichiro Sato ; Atsushi Iwata (2025): Cost analyses of plasma p-tau217 versus p-tau217/Aβ42 ratio using two-step approach in the Japanese health care system. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100572
ASSESSMENT OF CLINICAL AND NEUROIMAGING EFFICACY OF TREATMENT TARGETING TAU PATHOLOGY IN MILD COGNITIVE IMPAIRMENT AND MILD TO MODERATE ALZHEIMER’S DISEASE WITH HYDROMETHYLTHIONINE MESYLATE USING EXTERNAL CONTROL DATA
Bjoern O Schelter, Helen Shiells, Serena Lo, Nafeesa Nazlee, Emily Evans, Peter Bentham, Serge Gauthier, Henrik Zetterberg, Gordon K Wilcock, Lutz Froelich, Alistair Burns, Emer MacSweeney, Clive Ballard, Jin-Tai Yu, Tay Siew Choon, Vahe Asvatourian, Natalia Muehlemann, Jan Priel, Karin Kook, Tenecia Sullivan, Diane Downie, Sonya Miller, Carol Pringle, John M?D Storey, Tom Baddeley, Charles R Harrington, Roger Staff, Anca-Larisa Sandu, Claire Hull, Richard Stefanacci, Claude M Wischik, Alzheimer\'s Disease Neuroimaging Initiative
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BACKGROUND: Hydromethylthionine mesylate (HMTM) targets tau pathology and also has tau-independent symptomatic activity. A traditional randomised placebo-controlled trial (RCT) was precluded by loss of blinding due to urinary colouration and therapeutic activity at the minimum dose required to maintain blinding.
OBJECTIVE: To evaluate the efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer’s disease (AD).
METHODS: Because a traditional RCT was not feasible without loss of blinding, we compared HMTM 16 mg/day in TRx-237–039 with propensity score matched true placebo controls from the FDA-sponsored Critical Path for AD (CPAD) database with the same inclusion/exclusion criteria (protocol TRx-237–080). We also compared HMTM 16 mg/day with matched natural history controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and with a meta-analysis of placebo arms from trials in comparable populations in analyses specified prior to the 104-week database lock of TRx-237–039.
PARTICIPANTS: Propensity score matching yielded 127 pairs (HMTM n = 127; CPAD placebo n = 127) in the CPAD comparison, and 189 pairs in the ADNI comparison. A total of 218 receiving HMTM 16 mg/day were compared with meta-analytic controls (n = 1805–8567).
INTERVENTION: HMTM 16mg/day.
MEASUREMENTS: Primary outcomes in TRx-237–080 were change from baseline to 78 weeks in ADAS-Cog13 and whole brain volume (WBV). CDR-Sum of Boxes (CDR-SB) and CDR-Global were analysed at 104 weeks. ADAS-cog11 and WBV were analysed in ADNI comparisons, and ADAS-cog11, ADCS-ADL23, CDR-SB and WBV were analysed in meta-analytic comparisons.
RESULTS: Compared with matched CPAD placebo, HMTM 16 mg/day produced statistically significant differences in change on ADAS-Cog13 (p < 0.0001) and WBV at 78 (primary; p < 0.0001) and 104 weeks (p < 0.0001), and CDR-SB differed significantly overall (104-weeks; p < 0.001) and in MCI (p = 0.007). The odds of progressing to a more advanced CDR-Global stage were lower with HMTM (overall OR 0.31) and particularly in MCI (OR 0.15) versus CPAD placebo. Clinical and brain atrophy outcomes were similarly statistically significant in comparisons with ADNI case-matched natural history data and in meta-analytic comparisons.
CONCLUSION: Comparisons of HMTM treatment with CPAD, ADNI, and meta-analytic controls provide evidence consistent with clinical benefit HMTM. It has the potential to offer an accessible oral treatment option which could be delivered with minimal patient/physician burden.
CITATION:
Bjoern O Schelter ; Helen Shiells ; Serena Lo ; Nafeesa Nazlee ; Emily Evans ; Peter Bentham ; Serge Gauthier ; Henrik Zetterberg ; Gordon K Wilcock ; Lutz Froelich ; Alistair Burns ; Emer MacSweeney ; Clive Ballard ; Jin-Tai Yu ; Tay Siew Choon ; Vahe Asvatourian ; Natalia Muehlemann ; Jan Priel ; Karin Kook ; Tenecia Sullivan ; Diane Downie ; Sonya Miller ; Carol Pringle ; John M․D Storey ; Tom Baddeley ; Charles R Harrington ; Roger Staff ; Anca-Larisa Sandu ; Claire Hull ; Richard Stefanacci ; Claude M Wischik ; Alzheimer's Disease Neuroimaging Initiative (2025): Assessment of clinical and neuroimaging efficacy of treatment targeting tau pathology in mild cognitive impairment and mild to moderate Alzheimer’s disease with hydromethylthionine mesylate using external control data. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100560
PATHWAYS TO PARTICIPATION – A SCOPING REVIEW OUTLINING BARRIERS AND ENABLERS TO PARTICIPATION IN DEMENTIA RESEARCH
Lukas A. Duffner, Soraya Moradi-Bachiller, Dianne Gove, Ana M. Diaz-Ponce, Angela Bradshaw, Jean Georges
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BACKGROUND: Ongoing participant recruitment challenges in dementia research highlight the need to understand public perspectives on research participation. This scoping review explored existing literature on barriers and enablers to the recruitment and retention of participants in dementia studies.
METHODS: A scoping review was conducted in PubMed and PsycINFO, following the Arksey and O’Malley framework, using a keyword profile informed by a pilot search (full protocol available at osf.io/n8j4u). Abstract and full text screening were performed in duplicate and data were extracted using predefined criteria. Reported barriers and enablers were grouped into overarching themes. A panel of people with dementia and carers subsequently shared their perspectives on recruitment challenges and reflected on the review findings.
RESULTS: Forty-five publications were included for narrative synthesis, representing 112,011 participants (pooled mean age = 69.3 years; 64.8 % female). Most studies originated from the U.S. and focused on clinical dementia research, with an emphasis on recruitment rather than long-term retention. Barriers were grouped into eight themes: mistrust; fears, worries and concerns; awareness; beliefs and attitudes; practical and logistical constraints; study-related factors; informational barriers; and barriers related to carers and support systems. Enablers included internal motivators (e.g. altruism) and external facilitators (e.g. financial compensation or flexible scheduling).
CONCLUSIONS: While significant research gaps remain, many barriers to participation in dementia research appear modifiable. Targeted actions addressing these modifiable factors may enhance recruitment and retention, which may strengthen the inclusivity and impact of dementia research.
CITATION:
Lukas A. Duffner ; Soraya Moradi-Bachiller ; Dianne Gove ; Ana M. Diaz-Ponce ; Angela Bradshaw ; Jean Georges (2025): Pathways to participation – a scoping review outlining barriers and enablers to participation in dementia research. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100558
COMPARATIVE EFFECTS OF SOME PHARMACOLOGICAL AND NON-PHARMACOLOGICAL INTERVENTIONS ON COGNITIVE FUNCTION IN ALZHEIMER’S DISEASE: A BAYESIAN NETWORK META-ANALYSIS
Yuning Zhao, Guangxin Luo, Can Huang, Zhenyang Chen, Yu Wei, Qiaosen Chen, Fang Wang, Yong Gan, Xiaoxv Yin
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BACKGROUND: Given the growing global public health burden of Alzheimer’s disease, this study used the Bayesian network meta-analysis to assess the effects of pharmacological and non-pharmacological interventions on cognitive function in the population with Alzheimer’s disease.
METHODS: Two investigators screened the literature from English databases (PubMed, MEDLINE, Embase, Cochrane CENTRAL, and Web of Science) and three major Chinese bibliographical databases (China National Knowledge Infrastructure Database, Wanfang Database, and VIP Database). We assessed the risk of bias and publication bias of the selected literature. Subsequently, a Bayesian network meta-analysis and meta-regression were conducted to further investigate the comparative efficacy of different interventions on cognitive outcomes.
RESULTS: A total of 4788 cases were initially identified. Photobiomodulation [SMD=0.66, 95%CrI (0.29, 1.02)], enriching environment [SMD=0.69, 95%CrI (0.08, 1.31)], pharmacological therapy [SMD=0.36, 95%CrI (0.17, 0.55)], cognitive stimulation therapy [SMD=0.32, 95%CrI (0.11, 0.55)] and exercise therapy [SMD=0.28, 95%CrI (0.06, 0.51)] showed considerable enhancements in cognitive function among individuals with Alzheimer’s disease. Photobiomodulation and enriching environment stood out, with their effects more potent than those of other therapies, as indicated by the surface under the cumulative ranking curve — photobiomodulation clocked in at 87.3%, while enriching environment scored 83.8%, versus pharmacological therapy’s 54.7%.
CONCLUSIONS: Among the interventions evaluated, photobiomodulation and enriching environment were associated with better improvements in cognitive function than pharmacological therapy. Exercise therapy and cognitive stimulation therapy also demonstrated beneficial effects. Music therapy showed no statistical difference from the control group. In addition, the research developed an innovative approach to contrast pharmacological and non-pharmacological treatments for Alzheimer’s disease.
CITATION:
Yuning Zhao ; Guangxin Luo ; Can Huang ; Zhenyang Chen ; Yu Wei ; Qiaosen Chen ; Fang Wang ; Yong Gan ; Xiaoxv Yin (2025): Comparative effects of some pharmacological and non-pharmacological interventions on cognitive function in Alzheimer’s disease: A Bayesian network meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100564
ATNIVS BIOMARKER HETEROGENEITY IN REAL-WORLD PATIENTS RECEIVING LECANEMAB
Masanori Kurihara, Ryoko Ihara, Gen Yoshii, Ryosuke Shimasaki, Keiko Hatano, Taro Bannai, Fumio Suzuki, Kenji Ishibashi, Ko Furuta, Katsuya Satoh, Aya Midori Tokumaru, Kenji Ishii, Atsushi Iwata
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BACKGROUND: While amyloid-β (Aβ) biomarker positivity is sufficient before initiating anti-Aβ antibody therapy, recent revised criteria also highlight the importance of other biomarkers (ATNIVS) to understand heterogeneity in AD.
DESIGN, SETTING, AND PARTICIPANTS: We reviewed patients who attended our specialty clinic between December 2023 and October 2024. Some participated in tau PET study (18F-MK6240). MRI was assessed using Fazekas score. Remaining samples were analyzed for plasma neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and CSF α-synuclein seed amplification assay (SAA).
RESULTS: During the period, 200 attended and 147 proceeded to screening. Lecanemab was started in 93 of 108 A+ patients; mean age 74.2 years, 73.1% female. While all tested started on lecanemab were positive on amyloid PET, 21% had only regional positivity with lower Aβ burden (centiloid 31.3 ± 17.5 vs 67.6 ± 20.2) and higher age (79.2 ± 5.1 vs 73.3 ± 8.9). While all tested had CSF Aβ42/40 values below the single cut-off 0.067 in Japan, three (8.6%) had values close to the cutoff (0.059–0.067), all of whom were male. Other biomarkers also widely varied from normal to fully abnormal; CSF pTau181 (40.5–168 pg/mL, cut-off 56.5), tau PET-based Braak stage (0–VI), NfL (10.0–103.3 pg/mL), GFAP (121.9–652.5 pg/mL), Fazekas score (0–3), and positive α-synuclein SAA (25–33%). Some associations were indicated including higher Fazekas scores in amyloid PET regional-positive group and higher plasma NfL in CSF Aβ42/40 0.059–0.067 group.
CONCLUSIONS: We identified substantial heterogeneity in ATNIVS biomarker profiles among patients receiving lecanemab in a real-world setting.
CITATION:
Masanori Kurihara ; Ryoko Ihara ; Gen Yoshii ; Ryosuke Shimasaki ; Keiko Hatano ; Taro Bannai ; Fumio Suzuki ; Kenji Ishibashi ; Ko Furuta ; Katsuya Satoh ; Aya Midori Tokumaru ; Kenji Ishii ; Atsushi Iwata (2025): ATNIVS biomarker heterogeneity in real-world patients receiving lecanemab. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100567
KNOWLEDGE AND PERCEPTION OF DEMENTIA RISK AND PROTECTIVE FACTORS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Muhammed L. Sambou, Jolanda H.M. Dobbe, Elaine A.C. Albers, Kay Deckers, Lidia R. Arends, M. Arfan Ikram, Ellen M.A. Smets, Wichor M. Bramer, Jeremy A. Labrecque, Leonie N.C. Visser, Frank J. Wolters
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BACKGROUND: Optimal dementia risk reduction strategies benefit from sufficient public knowledge of risk factors and risk perception, but current public awareness is uncertain.
METHODS: In a systematic literature review on public knowledge and perception of dementia risk factors, we searched relevant databases for original research articles until 2024. When possible, we pooled study results using random effects meta-analysis, and explored sources of heterogeneity through meta-regression. Qualitative studies and studies about risk perception were analysed using narrative synthesis.
FINDINGS: Of 4996 articles screened, 155 were eligible for inclusion. Of these, 125 reported on knowledge of risk factors and 50 on risk perception, jointly providing data from 164,644 participants in 41 countries across 6 continents. Recognition of the 28 queried risk and protective factors was moderate, somewhat higher for lifestyle factors (medians: 38.5–71.5%) than for cardiovascular (9.9–66.9%) and environmental (25.4–44.4%) factors, but with large heterogeneity across queried factors. With the exception of physical activity (71.5%, IQR:46.9–88.3%), social isolation (66.6% [23.7–84.0%]) and traumatic brain injury (65.0% [18.0–76.7%]), recognition of all established modifiable risk factors for dementia from prespecified lists was below 50%, lowest for education (19.5% [7.8–54.9%]), air pollution (25.4% [16.3–41.0%]), and obesity (30.4% [27.0–43.0%]). Recall of risk factors (7 studies) was markedly lower than recognition. Meta-regression analyses showed no consistent differences by year of publication, or by participants’ age, gender, and educational attainment. Among 23 qualitative studies, limited knowledge emerged particularly regarding dementia-specific risk factors like hearing loss. Perceived risk was measured inconsistently across studies, but was generally moderate to high, along with notable worry about dementia in a large part of the older population.
CONCLUSIONS: Knowledge of dementia risk and protective factors in the general population remains limited. These findings call for population-level interventions, including educational campaigns, to enhance preventive strategies.
CITATION:
Muhammed L. Sambou ; Jolanda H.M. Dobbe ; Elaine A.C. Albers ; Kay Deckers ; Lidia R. Arends ; M. Arfan Ikram ; Ellen M.A. Smets ; Wichor M. Bramer ; Jeremy A. Labrecque ; Leonie N.C. Visser ; Frank J. Wolters (2025): Knowledge and perception of dementia risk and protective factors: a systematic review and meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100565
MULTIDIMENSIONAL MODELING OF BIOLOGICAL AGING: INTEGRATING GAIT, EYE MOVEMENT, REST-STATE FUNCTIONAL CONNECTIVITY, AND PLASMA BIOMARKERS IN NON-DEMENTIA OLDER ADULTS
Jingyi Lin, Yiliang Liu, Ziyu Ouyang, Xuan Yang, Sizhe Zhang, Tianyan Xu, Qijie Yang, Yuan Zhu, Meidan Wan, Xuewen Xiao, Xiangmin Fan, Beisha Tang, Lu Shen, Bin Jiao, Shilin Luo
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Accurate modeling of biological age has clinical value for risk stratification, personalized prevention, and intervention planning, promoting proactive healthcare for aging and age-related diseases. Because aging is multidimensional, robust and interpretable multimodal approaches are needed. We studied 908 non-dementia older adults (> 60 years), collecting data on gait, eye movements, resting-state functional connectivity (rs-FC), and plasma biomarkers (neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP). Fourteen gait features, two eye movement features, 19 rs-FC features, and plasma GFAP levels were significantly correlated with age (p < 0.05). Among single-domain models, eye movement features showed the strongest predictive performance (R2 = 0.606; MAE = 3.060). A combined multimodal model achieved markedly higher accuracy (R2 = 0.814; MAE = 1.902). These findings demonstrate that integrating physiological, neurological, and biomarker data substantially improves biological age modeling, supporting the development of comprehensive frameworks to assess aging better and guide timely, targeted preventive strategies.
CITATION:
Jingyi Lin ; Yiliang Liu ; Ziyu Ouyang ; Xuan Yang ; Sizhe Zhang ; Tianyan Xu ; Qijie Yang ; Yuan Zhu ; Meidan Wan ; Xuewen Xiao ; Xiangmin Fan ; Beisha Tang ; Lu Shen ; Bin Jiao ; Shilin Luo (2025): Multidimensional modeling of biological aging: integrating gait, eye movement, rest-state functional connectivity, and plasma biomarkers in non-dementia older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100566
STRUCTURAL SOCIAL FACTORS MODIFY THE ASSOCIATION BETWEEN ALZHEIMER’S PATHOLOGY AND COGNITIVE FUNCTION
Michelle Gerards, Lena Sannemann, Frank Jessen
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BACKGROUND: Social factors have been linked to cognitive decline and risk of dementia. However, our understanding of their impact on cognition in the context of Alzheimer’s disease (AD) pathology is still limited.
OBJECTIVES: This study examined whether two structural social factors, relationship status (RS) and living situation (LS), modify the association between AD pathology and cognition.
DESIGN: Observational, analysis of existing cohort data.
SETTING: Data were obtained from the National Alzheimer's Coordinating Center (NACC) and the Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study.
PARTICIPANTS: Participants with available data on cognitive performance, AD pathology, and structural social factors.
MEASUREMENTS: We used the Mini-Mental State Examination (MMSE), a widely used brief screening measure of global cognitive status. For the description of AD, postmortem neuropathology (NACC) reports, or amyloid PET (IDEAS) were used. RS and LS were coded according to the respective datasets. Group comparisons and regression models were used to evaluate interactions between RS or LS with AD pathology on cognition.
RESULTS: Across cohorts, up to 31% of individuals were not in a relationship, and up to 22% lived alone. Individuals in a relationship (RS+) or those who lived with someone (LS+) showed poorer cognitive performance than those not in a relationship (RS-) or living alone (LS-) at comparable levels of AD pathology. Interaction analyses indicated that the association between AD pathology and MMSE differed by LS, with LS+ being associated with slightly lower MMSE scores across pathology levels, an effect primarily driven by participants living with someone who is not a partner. In contrast, within the NACC cohort, RS+ individuals showed overall lower MMSE scores, while the association between AD pathology and MMSE was weaker compared to RS− individuals.
DISCUSSION: LS and RS showed differences in how AD pathology related to global cognitive status. Being in a relationship was linked to a weaker association between AD pathology and global cognitive status, whereas living with someone was associated with a lower global cognitive status at comparable levels of pathology. While the direction of these associations remains unclear, our findings suggest that the relationship between AD pathology and cognitive status may vary across different structural social contexts.
CITATION:
Michelle Gerards ; Lena Sannemann ; Frank Jessen (2025): Structural social factors modify the association between Alzheimer’s pathology and cognitive function. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100563
HYPOLIPIDEMICS REDUCE THE RATE OF ALZHEIMER\'S DISEASE DEVELOPMENT AND DEMENTIA PROGRESSION: A COHORT STUDY LINKED WITH GENETIC AND NEUROPATHOLOGICAL ANALYSES
Zohi Sternberg, Rebecca E. Podolsky, Jihnhee Yu, Shuangcheng Hua, Stanley Halvorsen, Bernhard J. Schaller
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BACKGROUND: High cholesterol contributes to the development and progression of dementia due to both Alzheimer's disease (A.D.) and vascular pathology. However, the effects of lipid-lowering regimen (LLR) on cognitive dysfunction and brain neuropathology are unknown.
OBJECTIVE: To investigate the effect of LLR on the conversion from normal to mild cognitive impairment (MCI), indicated by CDR-SOB of >0–2.5 (MCI), and the progression to dementia, indicated by CDR-SOB =>3 (10-year follow-up) and LLR effect on the rate of survival (15-year follow-up). Participants were stratified by age (≤70 years and >70 years), gender, and the presence of at least one copy of the APOE4 allele. We also analyzed the effect of LLR on brain neuropathology in participants, indicated by Braak staging, hippocampal atrophy, and CSF levels of total Tau. The differential effect of LLR, with or without cerebrovascular disease, lacunar infarct, or cystic infarction in the cognitive network, was analyzed.
METHODS: We have analyzed the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS).
RESULTS: In participants with CDR-SOB of >0–2.5, the use of hypolipidemic agents was associated with a reduced yearly increase in the CDR-SOB scores by 0.0088 (0.0038, 0.0138) unit (P < 0.001). This effect was more pronounced in participants with CDR-SOB =>3 showing a reduced yearly increase in the CDR-SOB scores by 0.1733 (0.1441, 0.2025) unit (P < 0.001) in LLR-users compared to non-users, and an increased rate of survival [HR: 0.822 (0.746, 0.906). P = 0.001]. The pattern persisted when participants were stratified based on age, gender, and the presence of APOE4. LLR had no significant effect on Braak staging scores, hippocampal atrophy, and total CSF Tau level, and was independent of the presence or absence of cerebrovascular disease, lacunar infarct, and cystic infarction in cognitive network.
CONCLUSION: Our results have implications for delaying cognitive dysfunction and halting the progression of dementia, regardless of the etiology being related to AD or vascular pathology.
CITATION:
Zohi Sternberg ; Rebecca E. Podolsky ; Jihnhee Yu ; Shuangcheng Hua ; Stanley Halvorsen ; Bernhard J. Schaller (2025): Hypolipidemics reduce the rate of Alzheimer's disease development and dementia progression: A cohort study linked with genetic and neuropathological analyses. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100555
AMYLOID-RELATED IMAGING ABNORMALITIES IN JAPANESE PATIENTS WITH ALZHEIMER’S DISEASE TREATED WITH LECANEMAB: A REAL-WORLD STUDY
Ryosuke Shimasaki, Masanori Kurihara, Taro Bannai, Keiko Hatano, Fumio Suzuki, Aya Midori Tokumaru, Kenji Ishii, Ryoko Ihara, Atsushi Iwata
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BACKGROUND: Although clinical trials have suggested a lower incidence of adverse events associated with Lecanemab in Asian populations compared to global cohorts, longitudinal real-world data across broader clinical indications are necessary to confirm these findings in routine practice.
OBJECTIVES: This study aimed to provide real-world evidence regarding the safety profile of Lecanemab in Japanese patients in a clinical setting.
DESIGN: A real-world observational study with a follow-up period of up to 18 months.
SETTING: A single center in Japan.
PARTICIPANTS: We included 120 Japanese patients who received Lecanemab between December 2023 and November 2025 and underwent at least one brain MRI before the fifth infusion.
MEASUREMENTS: Safety outcomes included amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation.
RESULTS: The mean age was 74.2 ± 7.9 years, and 89 (74%) were female. The majority of patients (88%) had a baseline CDR global score of 0.5. During follow-up, 81 patients completed the 12-month assessment. ARIA occurred in 24 patients (20%); ARIA-E with or without ARIA-H occurred in 5 patients (4%), and isolated ARIA-H occurred in 19 patients (16%). Crucially, no patients experienced symptomatic ARIA. All patients with ARIA-E who had available APOE data were ε4 carriers. Patients with ARIA had significantly lower baseline MMSE scores (p = 0.04), alongside non-significant trends toward higher plasma GFAP levels (p = 0.11) and higher deep white matter Fazekas scores (p = 0.05). IRRs occurred in 34 patients (28%), all of which were mild. Treatment was discontinued in 19 patients (16%), mainly due to disease progression (n = 8).
CONCLUSION: In this Japanese AD cohort, Lecanemab demonstrated a manageable safety profile in a real-world setting. In exploratory analyses, potential trends toward a higher frequency of ARIA were observed in patients with lower MMSE scores, higher plasma GFAP levels, and higher Fazekas scores, underscoring the importance of individualized risk assessment prior to therapy.
CITATION:
Ryosuke Shimasaki ; Masanori Kurihara ; Taro Bannai ; Keiko Hatano ; Fumio Suzuki ; Aya Midori Tokumaru ; Kenji Ishii ; Ryoko Ihara ; Atsushi Iwata (2025): Amyloid-related imaging abnormalities in Japanese patients with Alzheimer’s disease treated with Lecanemab: A real-world study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100562
DEMENTIA RISK FACTOR ASSESSMENT IN A LOCAL ALZHEIMER’S PREVENTION POPULATION: A GERMAN CROSS-SECTIONAL, OBSERVATIONAL STUDY
Lena Sannemann, Michelle Gerards, Lara Bohr, Frederic Brosseron, Claus Escher, Franziska Kalthegener, Theresa Müller, Alfredo Ramírez, Philip Zeyen, Frank Jessen, Ayda Rostamzadeh
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BACKGROUND: The risk for dementia is to a significant extent driven by potentially modifiable factors. Prevention strategies are increasingly aiming at individually tailored risk reduction approaches, particularly in light of emerging Brain Health Services for dementia prevention (dBHS).
METHODS: The cross-sectional observational study “Individual Risk Profiling for Alzheimer's and Dementia Prevention” (INSPIRATION) assessed the individual risk factors of 162 participants of the local Cologne Alzheimer Prevention Registry and provided individual feedback on risk profiles during a single visit. We analysed the frequency and patterns of risk factors and explored their association with cognition and Alzheimer’s disease (AD) plasma biomarkers.
FINDINGS: The most common risk factors in this population were obesity, non-adherence to a Mediterranean diet, low subjective sleep quality, subjective experience of stress, and hearing impairment. A principal component analysis (PCA) revealed six principal components (PC), which we labeled as (1) psychosocial factors, (2) blood pressure, (3) physical condition, (4) hearing impairment, (5) lifestyle, and (6) substance use. We found isolated associations between PCs, cognition, and AD plasma biomarkers.
INTERPRETATION: These findings provide initial insights into which risk factors may be most relevant and actionable for highly-educated and prevention-motivated populations likely to seek dBHS. Interventions addressing the domains of psychosocial factors, physical condition, and lifestyle may be particularly relevant to consider for a personally tailored risk reduction approach in comparable populations.
FUNDING: The study was funded by research funds of the Medical Faculty and the University Hospital Cologne, University of Cologne and the non-profit association Kölner Verein für seelische Gesundheit e.V.
CITATION:
Lena Sannemann ; Michelle Gerards ; Lara Bohr ; Frederic Brosseron ; Claus Escher ; Franziska Kalthegener ; Theresa Müller ; Alfredo Ramírez ; Philip Zeyen ; Frank Jessen ; Ayda Rostamzadeh (2025): Dementia risk factor assessment in a local Alzheimer’s prevention population: a German cross-sectional, observational study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100556
GLOBAL, REGIONAL, AND NATIONAL BURDEN OF DEMENTIA ATTRIBUTABLE TO MOOD DISORDERS: A COMPARATIVE RISK ASSESSMENT STUDY
Jing Wu, Jiali Zhou, Shiyi Shan, Ke Tang, Longzhu Zhu, Jiayao Ying, Xinyu Liu, Peige Song
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BACKGROUND: Mood disorders, particularly depressive and bipolar disorders, have emerged as potentially modifiable risk factors for dementia. However, the burden of dementia attributable to mood disorders remains unquantified. We aimed to quantify that burden among adults aged 45 years and older using a comparative risk assessment approach.
METHODS: A literature search was performed in PubMed, Embase, and MEDLINE to identify cohort studies that assessed the association between mood disorders and subsequent dementia from database inception to 9th April 2025. Random-effects models were used to derive pooled risk ratios (RRs). Assuming a 5-year lag between mood disorders and dementia onset, we calculated population attributable fractions (PAFs) and age-standardized disability-adjusted life year (DALY) rates (ASDRs) at global, regional, and national levels. Temporal trends in ASDR were analyzed using joinpoint regression to estimate average annual percentage change.
RESULTS: 77 articles were included. The pooled RR for all-cause dementia was 1.90 (95% confidence interval [CI]: 1.70, 2.12) for depressive disorders, and 3.10 (95% CI: 2.21, 4.35) for bipolar disorder. For dementia subtypes, depressive disorders showed an association with Alzheimer’s disease (RR: 2.57, 95% CI: 2.05, 3.23), and bipolar disorder was associated with vascular dementia (RR: 3.67, 95% CI: 2.42, 5.57). In 2016, the global PAFs of dementia attributable to depressive disorders were 4.79% (95% CI: 3.19%, 6.58%) in males and 5.56% (95% CI: 3.56%, 7.84%) in females. PAFs for bipolar disorder were 1.22% (95% CI: 0.65%, 2.01%) in males and 1.34% (95% CI: 0.71%, 2.18%) in females. In 2021, the global ASDR of dementia attributable to depressive disorders was 89.61 (95% CI: 34.80, 192.24) per 100,000 population, while the global ASDR for bipolar disorder was 15.91 (95% CI: 5.56, 37.87) per 100,000 population.
CONCLUSION: Since mood disorders are a substantial contributor to dementia burden, integrating mental health management into public health policies is essential.
CITATION:
Jing Wu ; Jiali Zhou ; Shiyi Shan ; Ke Tang ; Longzhu Zhu ; Jiayao Ying ; Xinyu Liu ; Peige Song (2025): Global, regional, and national burden of dementia attributable to mood disorders: a comparative risk assessment study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2025.8
BARRIERS AND FACILITATORS TO RECRUITMENT, ENGAGEMENT, AND RETENTION OF UNDERREPRESENTED POPULATIONS IN DEMENTIA PREVENTION RESEARCH: A SCOPING REVIEW
A.F. Rirash, S. Franzen, R. Bourdage, E. Kreuk, N.C. Visser, G.M. Babulal, E. van den Berg, J.M. Papma
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Underrepresented populations in dementia prevention research, including minoritized racial/ethnic groups, individuals with lower socioeconomic status, and others facing social and structural disadvantages, are disproportionately affected by dementia risk. This scoping review examined barriers and facilitators to recruitment, engagement, and retention of these populations in Alzheimer’s disease and related dementias (ADRD) prevention studies, synthesizing evidence from both empirical studies and review articles. Guided by PRISMA-ScR and the conceptual structure described by Gilmore-Bykovskyi et al., findings were synthesized from 19 reviews and 53 empirical studies. Findings were interpreted with attention to how overlapping factors—such as ethnicity, age, gender, and structural inequities—may influence study participation. Studies originated primarily from the United States (U.S.). Five key themes were identified: 1) mistrust, 2) stigma and limited research literacy, 3) logistical and financial constraints, 4) communication gaps and lack of team diversity, and 5) systemic-level barriers. Facilitators included culturally tailored outreach, long-term community partnerships, and inclusive study design. Retention strategies remain underreported, and little is known about the non-U.S. context. These findings highlight the need for context-specific, multi-level strategies that address the intersecting barriers faced by underrepresented groups to support equitable participation in dementia prevention research, and ultimately, dementia prevention.
CITATION:
A.F. Rirash ; S. Franzen ; R. Bourdage ; E. Kreuk ; N.C. Visser ; G.M. Babulal ; E. van den Berg ; J.M. Papma (2025): Barriers and facilitators to recruitment, engagement, and retention of underrepresented populations in dementia prevention research: a scoping review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100557
INCREASE IN HEALTHCARE UTILIZATION AND MEDICARE PAYMENT WITH PROGRESSION OF PRECLINICAL ALZHEIMER’S DISEASE
Julie Beyrer, Zachary Sheff, Nalin Payakachat, Julie M. Chandler, Yun-Fei Chen, Joanna Kubisiak, Angelina Lee, Karen C. Holdridge, Roy Yaari, Paul Aisen, Michael S. Rafii, Reisa A. Sperling, A4 and LEARN Study Teams
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BACKGROUND: Alzheimer’s disease (AD) begins with the preclinical stage (Stages 1 and 2) where individuals are cognitively unimpaired but have AD pathology. Healthcare utilization and medical cost of cognitively unimpaired (preclinical) AD have not been previously evaluated.
OBJECTIVES: To describe healthcare resource utilization (HRU) and Medicare payments among cognitively unimpaired individuals with and without elevated amyloid and to evaluate the association of AD progression with HRU and Medicare payments.
DESIGN: Retrospective cohort analysis of the randomized controlled trial (Anti-Amyloid Treatment in Asymptomatic AD [A4]) and companion observational study (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [LEARN]) linked with Medicare.
SETTING: Clinical trials sites in the United States.
PARTICIPANTS: 246 cparticipants with cognitively unimpaired AD in A4 and 121 amyloid-negative participants in LEARN Medicare cohorts.
MEASUREMENTS: Measures from Medicare claims included medical conditions (diagnosis codes), HRU (inpatient, emergency room, outpatient, professional, skilled nursing facility, home health), and Medicare payments. AD progression (or cognitive or functional decline) was measured using Clinical Dementia Rating Scale-Global Score (CDR-GS) in A4/LEARN and diagnosis codes for cognitive impairment, AD, and JEN Frailty Index (JFI) of ≥6 (high frailty) in Medicare data.
RESULTS: HRU and payments were overall similar between A4 and LEARN Medicare. Claims indicators suggesting AD progression in A4 Medicare were associated with higher inpatient, outpatient, emergency room, and home health utilization (any utilization) and increased number of inpatient stays. Payments were significantly greater in A4 Medicare with AD progression vs without progression: 45% payment increase for cognitive impairment (p=0.035) with a mean incremental cost of $140 per person per month (PPPM) (95% confidence interval [CI] $125-$155), 66% payment increase for AD (p=0.011) with a mean incremental cost of $207 PPPM (95% CI $188-$226), and 103% payment increase for high frailty (p<0.001) with a mean incremental cost of $303 PPPM (95% CI $283-$323).
CONCLUSIONS: Overall, individuals with cognitively unimpaired AD in A4 Medicare did not have increased utilization and payments vs LEARN. HRU and payments were significantly greater in A4 Medicare participants with AD progression indicators in claims vs those without progression. These results highlight the need for additional research on both health and economic impacts of progression in a real-world (routine care) cohort of individuals with cognitively unimpaired AD and the potential cost savings associated with effective therapy that delays AD progression in cognitively unimpaired AD.
CITATION:
Julie Beyrer ; Zachary Sheff ; Nalin Payakachat ; Julie M. Chandler ; Yun-Fei Chen ; Joanna Kubisiak ; Angelina Lee ; Karen C. Holdridge ; Roy Yaari ; Paul Aisen ; Michael S. Rafii ; Reisa A. Sperling ; A4 and LEARN Study Teams (2025): Increase in healthcare utilization and Medicare payment with progression of preclinical Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100547
ASSOCIATION OF THE CUMULATIVE MODIFIED LIFE’S ESSENTIAL 8 SCORE WITH COGNITIVE CHANGE: RESULTS FROM TWO LONGITUDINAL CO-HORTS
Yiwen Dai, Yuling Liu, Yang Pan, Menghan Zhu, Xuyang Diao, Xinqing Yang, Jingya Ma, Darui Gao, Yanyu Zhang, Mengmeng Ji, Yichi Zhang, Wuxiang Xie, Fanfan Zheng
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INTRODUCTION: Although a higher baseline Life’s Essential 8 (LE8) score is linked to better cognitive performance and slower decline, it remains unclear whether the cumulative LE8 score is associated with cognitive change in later life.
METHODS: We included 1345 participants from the Health and Retirement Study (HRS) and 2865 participants from the English Longitudinal Study of Ageing (ELSA). A modified LE8 score was constructed based on sleep, physical activity, smoking, body mass index, blood lipids, blood glucose, and blood pressure. The cumulative modified LE8 score was calculated using 8 years of LE8 assessments. The association between cumulative modified LE8 score and cognitive change was examined using the linear mixed model.
RESULTS: Results from the HRS and the ELSA demonstrated general consistency. Pooled analysis showed that a per SD increase in cumulative modified LE8 score was associated with a slower rate of decline in global cognition (pooled Beta=0.089 SD/year), executive function (pooled Beta=0.093 SD/year), memory (pooled Beta=0.050 SD/year), and orientation (pooled Beta=0.040 SD/year).
DISCUSSION: A higher cumulative modified LE8 score was associated with better late-life cognition, highlighting the importance of maintaining long-term optimal cardiovascular health for preventing cognitive decline.
CITATION:
Yiwen Dai ; Yuling Liu ; Yang Pan ; Menghan Zhu ; Xuyang Diao ; Xinqing Yang ; Jingya Ma ; Darui Gao ; Yanyu Zhang ; Mengmeng Ji ; Yichi Zhang ; Wuxiang Xie ; Fanfan Zheng (2025): Association of the cumulative modified life’s Essential 8 score with cognitive change: Results from two longitudinal cohorts. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100548
JPAD Volume 13, N°05 - 2026
EDITORIAL: IT’S TIME TO ADDRESS THE RECRUITMENT BOTTLENECK
Gregory Cooper
J Prev Alz Dis 2026;5(13)
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CITATION:
Gregory Cooper (2025): Editorial: It’s time to address the recruitment bottleneck. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100571
EVALUATING EVIDENCE-BASED RECRUITMENT STRATEGIES FOR ALZHEIMER’S DISEASE AND RELATED DEMENTIAS CLINICAL TRIAL RESEARCH: A LITERATURE REVIEW
Mireille Jacobson, Christina Deuschle, Desi Peneva, Alice Nuo-Yi Wang, Cooper Roache, Meghan Walsh, Phyllis Barkman Ferrell, Maria-Alice Manetas, Rema Raman, Paul Aisen, Dana Goldman
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryBACKGROUND: With the prevalence of Alzheimer’s disease and related dementias (ADRD) rising, prevention and treatment clinical trials are increasingly important. Yet inadequate participant recruitment to ADRD research—a leading cause of trial delays, suspensions, or discontinuations—continues to hinder innovation and increase costs. This literature review aimed to identify ADRD recruitment strategies that are effective and ineffective, based on quantitative outcomes, with the goal of optimizing recruitment and advancing recruitment science.
METHODS: PubMed, Google Scholar, relevant ADRD websites, and references were searched for studies meeting inclusion criteria—those reporting quantitative outcomes aimed at improving recruitment rates, timely recruitment, or representation. Reference lists from relevant systematic reviews and meta-analyses, including publications from leading researchers, were also examined. The Mixed Methods Appraisal Tool (MMAT) was used to assess evidence quality.
RESULTS: The search yielded 965 publications, of which 50 met inclusion criteria. Few studies reported recruitment methods for pharmacological trials, and many lacked sufficient detail or standardized reporting to assess quality using MMAT criteria, making it difficult to determine effectiveness. Recruitment efforts deemed successful by study authors often relied on multi-pronged approaches integrating community engagement, structured outreach, and digital tools. However, evidence for effective and scalable strategies remains limited.
CONCLUSION: Advancing ADRD recruitment science requires progress in two key areas: embedding recruitment evaluation directly into trial protocols and encouraging broader sharing of recruitment data. Routine practices, such as publishing recruitment outcomes and adopting standardized reporting, can help close the evidence gap. These approaches enable comparison, replication, and generalizability of effective strategies, ultimately accelerating progress in ADRD research.
CITATION:
Mireille Jacobson ; Christina Deuschle ; Desi Peneva ; Alice Nuo-Yi Wang ; Cooper Roache ; Meghan Walsh ; Phyllis Barkman Ferrell ; Maria-Alice Manetas ; Rema Raman ; Paul Aisen ; Dana Goldman (2026): Evaluating evidence-based recruitment strategies for Alzheimer’s disease and related dementias clinical trial research: A literature review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100532
EDITORIAL: MOVING TOWARD A MORE RIGOROUS SCIENCE OF RECRUITMENT IN CLINICAL RESEARCH. COMMENTARY ON “EVALUATING EVIDENCE-BASED RECRUITMENT STRATEGIES FOR ALZHEIMER’S DISEASE AND RELATED DEMENTIAS CLINICAL TRIAL RESEARCH: A LITERATURE REVIEW”
Jaime Perales-Puchalt, Eric D. Vidoni
J Prev Alz Dis 2026;5(13)
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CITATION:
Jaime Perales-Puchalt ; Eric D. Vidoni (2025): Editorial: Moving toward a more rigorous science of recruitment in clinical research. Commentary on “Evaluating evidence-based recruitment strategies for Alzheimer’s disease and related dementias clinical trial research: a literature review”. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100561
POINT OF VIEW : HEALTHY LONGEVITY, INTRINSIC CAPACITY, GEROSCIENCE AND ALZHEIMER’S DISEASE PREVENTION
Bruno Vellas
J Prev Alz Dis 2026;5(13)
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CITATION:
Bruno Vellas (2025): Point of View: Healthy longevity, intrinsic capacity, geroscience and Alzheimer’s disease prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100570
MEMORY CONSOLIDATION AND ARIA IN INDIVIDUALS RECEIVING ANTI-AMYLOID MONOCLONAL ANTIBODIES
Marc W Haut, Camila Vieira Ligo Teixeira, Patrick D. Worhunsky, Rashi I. Mehta, Joseph E. Malone, Melanie Ward, Cierra M. Keith, Holly E. Phelps, Stephanie Pockl, Nafiisah Rajabalee, Khalid Sharif, Gary Marano, Pierre-Francois D’Haese, Ali R. Rezai
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryAmyloid related imaging abnormalities (ARIA) are the most significant risk associated with the use of anti-amyloid monoclonal antibodies (MAB) for Alzheimer’s disease (AD). Currently, the presence of the APOE ε4 allele is the best predictor for the development of ARIA. However, the degree of baseline memory impairment has not been fully explored as a risk factor for ARIA. Here, we examined MAB outcomes in a memory clinic population and compared patients with AD who developed ARIA to a case-matched group who did not develop ARIA. Participants who developed ARIA had greater numbers of recall intrusions and false positives, both markers for memory consolidation, at baseline than those who did not develop ARIA. We also observed greater baseline hippocampal and supplementary motor cortical atrophy with ARIA. These differences remained when controlling for the APOE ε4 allele and the presence of pretreatment microhemorrhages. Further investigation of memory impairment and associated brain atrophy is warranted to understand ARIA risk and MAB outcomes in AD.
CITATION:
Marc W Haut ; Camila Vieira Ligo Teixeira ; Patrick D. Worhunsky ; Rashi I. Mehta ; Joseph E. Malone ; Melanie Ward ; Cierra M. Keith ; Holly E. Phelps ; Stephanie Pockl ; Nafiisah Rajabalee ; Khalid Sharif ; Gary Marano ; Pierre-Francois D’Haese ; Ali R. Rezai (2026): Memory Consolidation and ARIA in Individuals Receiving Anti-amyloid Monoclonal Antibodies. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100519
AMYLOID SPATIAL EXTENT WITH FLORBETAPIR-PET FOR EARLY DETECTION OF PRECLINICAL ALZHEIMER’S DISEASE
Emma G. Thibault, Grace Del Carmen Montenegro, J?Alex Becker, Julie C? Price, Brian C. Healy, Bernard J. Hanseeuw, Rachel F. Buckley, Heidi I.L. Jacobs, Michael J. Properzi, Reisa A. Sperling, Keith A. Johnson, Michelle E. Farrell
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryBACKGROUND: Prevention of Alzheimer’s disease (AD) requires biomarkers sensitive to the earliest amyloid-β (Aβ) deposits.
OBJECTIVES: To characterize performance of a recently-developed Aβ-PET spatial extent metric (EXT) for early Aβ detection using 18[F]-florbetapir (FBP)-PET, evaluating its sensitivity, reliability, and associations with plasma pTau217, tau-PET, and cognition.
DESIGN: Longitudinal study with up to 5.5 years of PET, plasma and cognitive measures.
SETTING: The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) Study and its companion screen-fail study Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) conducted across 67 international sites.
PARTICIPANTS: 1118 cognitively unimpaired older adults from the A4 placebo arm and LEARN.
MEASUREMENTS: EXT (% of neocortex above region-specific thresholds), global Aβ SUVR, plasma pTau217, medial temporal (MTL) and temporal neocortical (nTEMP) tau-PET SUVR, and Preclinical Alzheimer Cognitive Composite (PACC).
RESULTS: EXT showed high cross-sectional reliability and longitudinal stability. Using EXT reclassified 21.4% of SUVR-participants from Aβ− to Aβ+ and predicted who would progress to SUVR+ 5.5 years later with 83% sensitivity and 94% specificity. In SUVR− individuals, higher pTau217 associated with greater SUVR only within EXT+ individuals. Baseline EXT outperformed SUVR in predicting MTL tau proliferation. For neocortical tau SUVR and PACC change, EXT was the better predictor in earlier Aβ stages (while Aβ spread) while SUVR was superior later (after Aβ was widespread).
CONCLUSIONS: EXT is a robust, generalizable PET metric that detects Aβ before global positivity and early Aβ-related changes in tau and cognition, supporting its relevance for trial enrichment and early therapeutic monitoring in AD prevention trials.
CITATION:
Emma G. Thibault ; Grace Del Carmen Montenegro ; J․Alex Becker ; Julie C․ Price ; Brian C. Healy ; Bernard J. Hanseeuw ; Rachel F. Buckley ; Heidi I.L. Jacobs ; Michael J. Properzi ; Reisa A. Sperling ; Keith A. Johnson ; Michelle E. Farrell (2026): Amyloid spatial extent with florbetapir-PET for early detection of preclinical Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100529
DISCORDANCE IN AMYLOID POSITIVITY BETWEEN VISUAL READS AND CENTILOIDS: IMPACT OF WHITE MATTER UPTAKE
Arnaud Charil, Todd M. Nelson, Anthonin Reilhac, Viswanath Devanarayan, Shobha Dhadda, Michael C. Irizarry, Lynn D. Kramer, Larisa Reyderman
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryBACKGROUND: The visual interpretation of amyloid PET scans, or visual read (VR), is the most common technique used in clinical practice to identify the presence of cerebral amyloid plaques. Amyloid status (positive or negative) determined by VR or using a Centiloid (CL) cut-off shows high overall concordance. However, discordant cases can occur where the VR is positive, but the CL is below the positivity cut-off, or vice versa.
OBJECTIVES: The objective of this analysis was to evaluate the rate of discordance and explore potential causes, particularly the role of amyloid tracer uptake in the white matter (WM), when determining amyloid status using VR and CL in screening for the elenbecestat phase 3 studies in early Alzheimer's disease (AD).
DESIGN: Amyloid PET scans using either Florbetapir (Amyvid™), Florbetaben (Neuraceq™) or Flutemetamol (Vizamyl™) from 3,232 participants (1507 VR- and 1725 VR+) with cognitive impairment screened for the elenbecestat phase 3 studies in early AD were visually interpreted at screening by trained neuroradiologists and quantified using CL values.
SETTING: Academic and clinical centers.
INTERVENTIONS/MEASUREMENTS: Quantitatively, amyloid positivity was defined as CL > 32.21. The number of positive cortical regions was determined by counting the number of regions with a standardized uptake value ratio (SUVr) that exceeded 1.17. PET SUVr levels in the cerebral WM were measured using an eroded WM region of interest (ROI). Statistical tests were conducted to detect differences among the four concordance groups, defined by the relationship of VR and CL status (positive or negative). Additionally, tests examined the relationship between uptake in the WM and rates and type of discordance. Receiver operating characteristic (ROC) analysis and DeLong’s test were also used to examine the effect of different tracers on the discordant rates.
RESULT: Discordance was observed in 6.53% of cases (n=211), with VR+/CL- in 4.61% (n=149) and VR-/CL+ in 1.92% (n=62). VR+/CL- discordant cases had significantly fewer amyloid-positive cortical regions compared to both VR+/CL+ and VR-/CL+ cases. VR-/CL+ cases had a significantly higher WM uptake than VR-/CL- and VR+/CL- cases. Our findings revealed a relationship between WM uptake and rates and types of discordance. High WM uptake can erroneously lead to CL+, due to gray matter (GM) contamination from the WM, and VR- status, due to reduced contrast between WM and GM, resulting in VR-/CL+ cases. Conversely, low WM uptake can result in an underestimation of CL values, inaccurately classifying a scan as CL-, and at the same time, the increased contrast may result in a VR+, thereby increasing the occurrence of discordant VR+/CL- cases.
CONCLUSION: Variations in WM uptake significantly contribute to discordances by introducing positive or negative bias in CL values and altering the GM to WM contrast, which forms the basis of the VR. Nevertheless, the rates of discordant cases are low and VR represents a robust and validated method to determine the presence of amyloid deposition. VR enables enrolling patients with amyloid beta pathology, as seen on amyloid PET scans, whereas CL scaling was developed to provide standardized units that more consistently characterize longitudinal amyloid‑β change. These findings reflect the complementary roles of VR and CL in amyloid PET evaluation, with implications for refining diagnostic accuracy and disease monitoring in AD clinical trials and practice.
CITATION:
Arnaud Charil ; Todd M. Nelson ; Anthonin Reilhac ; Viswanath Devanarayan ; Shobha Dhadda ; Michael C. Irizarry ; Lynn D. Kramer ; Larisa Reyderman (2026): DISCORDANCE IN AMYLOID POSITIVITY BETWEEN VISUAL READS AND CENTILOIDS: IMPACT OF WHITE MATTER UPTAKE. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100530
INTERIM ANALYSIS OF ALL-CASE POST-MARKETING SURVEILLANCE STUDY IN JAPAN: LECANEMAB IN PATIENTS WITH EARLY ALZHEIMER’S DISEASE
Atsushi Iwata, Yukinori Sakata, Kinuyo Koizumi, Akira Endo, Weijie Kuang, Kenta Sumitomo, Mika Ishii
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryBACKGROUND: Lecanemab is a monoclonal antibody targeting amyloid-beta protofibrils, indicated for patients with mild cognitive impairment (MCI) and mild dementia due to Alzheimer’s disease.
OBJECTIVES: This study reports interim findings of an ongoing, multicenter, prospective, observational post-marketing study for all patients treated with lecanemab in routine clinical practice in Japan, focusing on amyloid-related imaging abnormalities (ARIAs) and infusion-related reactions primarily observed during up to 28 weeks after treatment initiation.
METHODS: Patients treated with lecanemab at any medical institutions across Japan are included in the study. Data are collected using an electronic data capture system via standardized case report forms (CRFs). Study items included the incidence of ARIA, ARIA-edema or effusion (-E), ARIA-hemorrhage (-H: cerebral microhemorrhages, superficial siderosis, and macrohemorrhage), and infusion-related reactions, reported as adverse drug reactions.
RESULTS: As of July 5, 2025, CRFs from 2675 patients were collected, of whom 2672 had data available for the interim analysis. The median age was 76.0 years, and 62.6 % (1672/2672) of patients were diagnosed with MCI. At Week 28, 7.3 % (195/2672) of patients discontinued treatment, with a mean treatment duration of 189.6 ± 34.4 days. Among 2634 patients confirmed to have undergone MRI scans after treatment initiation, ARIA was observed in 7.1 % (188/2634) of patients, ARIA-E in 3.0 % (78/2634), and ARIA-H in 5.2 % (137/2634). Serious ARIA-H (macrohemorrhage) occurred in two patients (0.1 %). Infusion-related reactions were observed in 17.0 % (455/2672), including 0.7 % (18/2672) serious cases. The proportion of patients who experienced ARIA was highest in patients with apolipoprotein E (APOE) ε4 homozygotes.
CONCLUSION: This interim analysis represents one of the largest real-world lecanemab cohorts reported globally to date. Although absolute rates are not directly comparable with those from clinical trials, the trends in ARIA distributions across APOE genotypes and infusion-related reactions were comparable to those observed in clinical trials.
CITATION:
Atsushi Iwata ; Yukinori Sakata ; Kinuyo Koizumi ; Akira Endo ; Weijie Kuang ; Kenta Sumitomo ; Mika Ishii (2026): Interim analysis of all-case post-marketing surveillance study in Japan: lecanemab in patients with early Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100541
CHARACTERISTICS OF INFUSION-RELATED REACTIONS TO LECANEMAB IN EARLY ALZHEIMER’S DISEASE: A MULTICENTER REAL-WORLD STUDY IN NORTHWESTERN CHINA
Peijie Liu, Jie Liu, Jin Wang, Ying Du, Zhirong Liu, Hong Zhang, Aiqin Zhu, Gejuan Zhang, Xinling Meng, Chunmei Zhao, Weiping Zhang, Liangjun Dang, Wei Zhang, Qiumin Qu, Yan Qu
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryBACKGROUND: Infusion-related reactions (IRRs) represent the most common adverse events associated with lecanemab. However, real-world data on IRR characteristics and risk factors in Asian populations, particularly Chinese, remain scarce.
METHODS: In a multicenter prospective registry, 139 patients with early Alzheimer’s disease (AD) receiving lecanemab were included. IRRs were physician-confirmed. Multivariable logistic regression identified independent predictors.
RESULTS: The cumulative IRR incidence was 12.36 %, highest at the first infusion (17.3 %) and decreased significantly thereafter (P < 0.001). Fever (54.2 %) and dizziness (16.7 %) were the most common symptoms. 45.8 % of IRRs occurred 2–24 hours after infusion. All IRRs were mild (Grade 1) and self-limited. Hypertension (OR = 5.017, P = 0.007) and higher Fazekas score (OR = 2.734, P = 0.017) were independently associated with IRR.
DISCUSSION: In this Chinese real‑world cohort, lecanemab‑associated IRRs were less frequent, mild, and delayed. Hypertension and white‑matter hyperintensity severity emerged as key risk factors, underscoring the potential role of cerebrovascular health in IRR susceptibility.
CITATION:
Peijie Liu ; Jie Liu ; Jin Wang ; Ying Du ; Zhirong Liu ; Hong Zhang ; Aiqin Zhu ; Gejuan Zhang ; Xinling Meng ; Chunmei Zhao ; Weiping Zhang ; Liangjun Dang ; Wei Zhang ; Qiumin Qu ; Yan Qu (2026): Characteristics of infusion-related reactions to lecanemab in early Alzheimer’s disease: A multicenter real-world study in Northwestern China. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100542
PREVENTION OF DEMENTIA USING MOBILE PHONE APPLICATIONS (PRODEMOS) – A HEALTH-ECONOMIC COST-UTILITY ANALYSIS IN PEOPLE AGED 55–75 YEARS WITH LOW SOCIO-ECONOMIC STATUS
Ron Handels, Marieke Hoevenaar-Blom, Manshu Song, Carol Brayne, Eric Moll van Charante, Fiona E. Matthews, Junfang Xu, Linus Jönsson, Nicola Coley, Rachael Brooks, Xuening Jian, Tingting Qin, Youxin Wang, Wei Wang, Edo Richard, Anders Wimo, PRODEMOS study group
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryINTRODUCTION: We aimed to explore the potential incremental cost-effectiveness of the PRODEMOS coach-supported mobile health intervention for primary prevention of dementia versus standard of care provided to people aged 55–75 years with low socio-economic status (SES) in the United Kingdom (UK), and any SES in China.
METHODS: 12–18-month PRODEMOS trial (ISRCTN15986016) efficacy outcomes on hypertension, obesity, hypercholesterolemia, physical inactivity and smoking were extrapolated to lifetime impact on dementia onset, myocardial infarction, stroke and death using a health-economic open-source simulation model.
RESULTS: Simulated outcomes showed dementia cases were avoided (UK = -206 (-658 to 281), China = -140 (-456 to 205) per 100,000 persons) and disease-free time was gained for dementia, myocardial infarction and stroke (mean months per person UK = 0.4, 0.0 and 0.0; China = 0.2, 0.0 and 0.0 respectively). Assuming a maximum intervention duration of 10 years with a 10 % annual non-adherence rate, the incremental net health benefit in the UK (-0.190) and China (-0.009) indicated a potential lack cost-effectiveness.
LIMITATIONS: Our method was limited by strong assumptions regarding causality and sustained effectiveness, lack of some country-specific input estimates, and the lack of probabilistic analysis.
CONCLUSION: The PRODEMOS coach-supported mobile health intervention for the primary prevention of dementia, aimed at people aged 55 to 75 years with low SES in the UK and those of any SES in China, may potentially lack cost-effectiveness in both countries. However, lack of data required strong assumptions regarding causality and sustained effectiveness, which limited policy recommendations.
CITATION:
Ron Handels ; Marieke Hoevenaar-Blom ; Manshu Song ; Carol Brayne ; Eric Moll van Charante ; Fiona E. Matthews ; Junfang Xu ; Linus Jönsson ; Nicola Coley ; Rachael Brooks ; Xuening Jian ; Tingting Qin ; Youxin Wang ; Wei Wang ; Edo Richard ; Anders Wimo ; PRODEMOS study group (2026): Prevention of dementia using mobile phone applications (PRODEMOS) – a health-economic cost-utility analysis in people aged 55–75 years with low socio-economic status. The Journal of Frailty and Aging (JFA). https://doi.org/10.1016/j.tjpad.2026.100526
NUTRITIONAL SUPPLEMENTS AND COGNITION IN HEALTHY AGING AND MILD COGNITIVE IMPAIRMENT PATIENTS: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS
Xing Liu, Chenyi Yang, Xinyi Wang, Huihui Liao, Huan Liu, Ji Ma, Yi Sun, Haiyun Wang
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryBACKGROUND: Nutritional supplementation is increasingly regarded as a potential strategy to preserve or enhance cognitive function in individuals with healthy aging and mild cognitive impairment (MCI). However, its overall efficacy remains uncertain due to inconsistent findings across clinical trials.
METHODS: In accordance with the guidelines outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Network Meta-Analyses, we conducted a comprehensive systematic search. Our inclusion criteria focused on randomized controlled trials (RCTs) that examined the impact of nutrient supplementation on cognitive function within healthy aging and MCI patients. The primary outcome of interest was the change in cognitive function, while the secondary outcome involved alterations in blood biochemical markers (e.g., homocysteine, vitamin B12, and serum folate levels).
RESULTS: The meta-analysis results indicated that docosahexaenoic acid (DHA)+eicosapentaenoic acid (EPA)+vitamin E+tryptophan+melatonin, as well as melatonin alone, significantly enhanced global cognitive function. Additionally, DHA, folic acid+DHA, and the DHA+EPA+vitamin E+tryptophan+melatonin were all effective in augmenting memory. DHA alone was found to be beneficial in improving processing speed, whereas vitamin D3 was associated with improvements in visuospatial function. Notably, sensitivity analyses revealed that while most domain-specific effects remained stable, the rankings of certain small-sample interventions were sensitive to study duration and sample size. Supplementation with folic acid, vitamin B12, and vitamin B6, whether administered individually or in combination, resulted in varying improvements in blood biomarkers, including homocysteine, vitamin B12, and serum folate levels.
CONCLUSIONS: Nutritional supplementation demonstrates nuanced, domain-specific benefits rather than universal cognitive enhancement. While specific multi-nutrient combinations show potential, their effects are significantly influenced by baseline cognitive status, age, and intervention duration. Our findings suggest that nutritional strategies should be tailored to individual cognitive profiles, emphasizing the need for personalized interventions and further high-quality, longitudinal trials to confirm long-term clinical impact.
CITATION:
Xing Liu ; Chenyi Yang ; Xinyi Wang ; Huihui Liao ; Huan Liu ; Ji Ma ; Yi Sun ; Haiyun Wang (2026): Nutritional supplements and cognition in healthy aging and mild cognitive impairment patients: a systematic review and network meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100518
SOCIODEMOGRAPHIC DIFFERENCES IN DEMENTIA PREVENTION KNOWLEDGE IN GERMANY: IMPLICATIONS FOR TARGETED HEALTH COMMUNICATION
Pauline Albus, Ann-Kristin Folkerts, Josef Kessler, Sebastian Köhler, Elke Kalbe
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryBACKGROUND: Dementia is a leading cause of disability and mortality worldwide. While the disorder is widely recognized, public awareness of modifiable risk and potentially protective factors remains limited. This is despite evidence that a substantial proportion of cases could be prevented or delayed by modifying personal risk factors. To date, the influence of sociodemographic factors on knowledge about dementia prevention has not been sufficiently examined, particularly in Germany, leaving a critical gap for targeted public health strategies.
OBJECTIVES: To assess awareness of the preventability of dementia and to evaluate knowledge of risk and protective factors in the German population, with particular focus on the influence of age, sex, and education.
DESIGN: Online, cross-sectional survey study.
SETTING: German population. A link to the survey was distributed nationwide via e-mail, flyers, and social media.
PARTICIPANTS: Adults aged ≥18 years without diagnosed cognitive impairment. A total of 2610 individuals completed the survey, of whom 2515 (mean age 52.5 years, range 18–95, 69.8% female) were included in the analysis.
MEASUREMENTS: Awareness of dementia, risk factors, and preventability was assessed using two dichotomous and three Likert-scale items. Knowledge of 23 evidence-based risk and protective factors (plus sham items) was measured with Likert-scale items. Composite knowledge scores were derived from these items, including separate subscores for medical and lifestyle-related risk factors. Preferred information dissemination sources were assessed using a multiple-choice item. Analyses included descriptive statistics and regression models with age, sex, and education as predictors.
RESULTS: While almost all respondents (98.2%) affirmed knowing what dementia is, only 73% affirmed awareness of risk-modifying factors, with substantial subgroup differences. Nearly 38% did not agree that dementia can be prevented, including a higher proportion of those aged ≥75 years (52%). Lifestyle factors, such as physical, mental, and social activity and diet, were most frequently recognized (>75%), whereas medical and environmental risks (e.g., cardiovascular disease, kidney disease, air pollution) were consistently underrecognized (<50%). Overall, younger age, female sex, and higher education were predictors of significantly higher knowledge scores, with education showing the strongest effect. Preferred information sources also differed systematically; lower-educated participants and men were more likely to rely on general practitioners, while higher-educated groups preferred digital resources and specialized organizations.
CONCLUSIONS: Compared with findings from previous German surveys, awareness of dementia preventability is higher in the present sample; however, knowledge about specific influencing factors—particularly medical—remains limited. As awareness, knowledge, and preferred information channels differ across age, sex, and education groups, educational efforts should be tailored accordingly.
CITATION:
Pauline Albus ; Ann-Kristin Folkerts ; Josef Kessler ; Sebastian Köhler ; Elke Kalbe (2026): Sociodemographic differences in dementia prevention knowledge in Germany: Implications for targeted health communication. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100517
PLASMA GFAP OUTPERFORMS CSF GFAP IN DETECTING AMYLOID PATHOLOGY AND IS ASSOCIATED WITH INCREASED RISK OF CLINICAL PROGRESSION IN EARLY ALZHEIMER’S DISEASE
Arda C. Cetindag, Carola G. Schipke, Hermann Esselmann, Niels Kruse, Jens Wiltfang, Anja Schneider, Klaus Fliessbach, Carolin Miklitz, Franziska Maier, Katharina Buerger, Daniel Janowitz, Michael Ewers, Sophia Stöcklein, Robert Perneczky, Boris-Stephan Rauchmann, Carolin Kurz, Stefan Teipel, Ingo Kilimann, Doreen Goerss, Christoph Laske, Sebastian Sodenkamp, Elham Najafpour, Michael Wagner, Sandra Roeske, Ingo Frommann, Melina Stark, Frederic Brosseron, Alfredo Ramirez, Luca Kleineidam, Josef Priller, Eike Jakob Spruth, Maria Gemenetzi, Slawek Altenstein, Emrah Düzel, Wenzel Glanz, Enise I. Incesoy, Michaela Butryn, Chris Bauer, Frank Jessen, Oliver Peters
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryBACKGROUND: Early and accurate detection of Alzheimer’s disease (AD) is essential for timely intervention and development of disease-modifying treatments. The DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) provides a deeply phenotyped cohort covering preclinical and early clinical stages, including subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Astrocyte reactivity and its biomarkers, particularly glial fibrillary acidic protein (GFAP), have gained increasing attention in AD research; however, the relationship between GFAP and amyloid in early disease, as well as its potential prognostic value beyond its association with amyloid status, remains insufficiently understood.
OBJECTIVES: To evaluate the performance of CSF and plasma GFAP across early disease stages, compare these measures according to amyloid status, and assess the prognostic value of GFAP for clinical progression across diagnostic stages during longitudinal follow-up.
SETTING: This study used data from the multicenter DELCODE cohort in Germany, including participants with available plasma and/or CSF samples and standardized clinical, cognitive, imaging, and biomarker assessments.
MEASUREMENTS: GFAP concentrations in plasma and CSF were quantified using validated immunoassay platforms. Standard CSF AD biomarkers and ApoE genotype were measured using established assays. Amyloid status was defined by the CSF Aβ42/40 ratio. Longitudinal follow-up occurred annually for up to ∼10 years, with clinical conversion determined according to NIA-AA criteria.
RESULTS: Plasma and CSF GFAP increased across the AD continuum, with higher levels in MCI and AD (p < 0.001). Plasma GFAP showed a stronger association with amyloid status than CSF GFAP across all groups. In MCI, plasma GFAP combined with age and ApoE4 yielded an AUC of 0.87. Elevated plasma GFAP predicted increased risk of conversion to MCI (HR = 2.19, p < 0.001; adjusted HR = 1.70, p = 0.0056) and AD dementia (HR = 3.5; adjusted HR = 2.49 both p < 0.001).
CONCLUSION: Plasma GFAP is a sensitive, minimally invasive biomarker with diagnostic relevance for amyloid detection and prognostic relevance for clinical progression in early AD.
CITATION:
Arda C. Cetindag ; Carola G. Schipke ; Hermann Esselmann ; Niels Kruse ; Jens Wiltfang ; Anja Schneider ; Klaus Fliessbach ; Carolin Miklitz ; Franziska Maier ; Katharina Buerger ; Daniel Janowitz ; Michael Ewers ; Sophia Stöcklein ; Robert Perneczky ; Boris-Stephan Rauchmann ; Carolin Kurz ; Stefan Teipel ; Ingo Kilimann ; Doreen Goerss ; Christoph Laske ; Sebastian Sodenkamp ; Elham Najafpour ; Michael Wagner ; Sandra Roeske ; Ingo Frommann ; Melina Stark ; Frederic Brosseron ; Alfredo Ramirez ; Luca Kleineidam ; Josef Priller ; Eike Jakob Spruth ; Maria Gemenetzi ; Slawek Altenstein ; Emrah Düzel ; Wenzel Glanz ; Enise I. Incesoy ; Michaela Butryn ; Chris Bauer ; Frank Jessen ; Oliver Peters (2025): Plasma GFAP outperforms CSF GFAP in detecting amyloid pathology and is associated with increased risk of clinical progression in early Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100544
PERFORMANCE OF A FULLY AUTO-MATED PLASMA TAU PHOSPHORY-LATED AT THREONINE 217 IMMU-NOASSAY TO REFLECT AMYLOID-BETA BURDEN IN AN UNSELECTED COHORT REPRESENTATIVE OF CLI-NICAL PRACTICE
Sayuri Hortsch, Annunziata Di Domenico, Niels Borlinghaus, David Caley, Laura Kaminioti-Dumont, Sara Bohn Jeppesen, Armand González-Escalante, Craig Ritchie, Kristian Steen Frederiksen, Marc Suárez-Calvet
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryBACKGROUND: With the emergence of disease-modifying anti-amyloid-beta (Aβ) therapies for Alzheimer’s disease (AD), early and accurate quantitative measures of Aβ burden are critical. Blood-based biomarkers are a scalable and minimally invasive diagnostic solution; plasma tau phosphorylated at threonine 217 (pTau217) is a promising marker for Aβ pathology. The clinical performance of the prototype ElecsysⓇ Phospho-Tau (217P) Plasma immunoassay (Roche Diagnostics) to detect Aβ burden was investigated in an unselected cohort reflective of clinical practice.
METHODS: Plasma was prospectively collected from participants aged 55 to 80 years with objective or subjective cognitive decline under evaluation for AD. Participants were recruited at multiple clinical sites spanning primary and secondary care. Plasma pTau217 concentrations measured using the prototype pTau217 plasma immunoassay were compared with amyloid positron emission tomography centiloid-based classification at different cutoffs, with further analyses performed at centiloid cutoff 30.
OUTCOMES: Among 588 participants, plasma pTau217 demonstrated high concordance with centiloid-based classification at selected cutoffs. The discriminative ability of plasma pTau217 to detect Aβ pathology peaked at centiloid cutoff 32 (area under the curve=0.933). Subgroup analyses at centiloid cutoff 30 demonstrated good discrimination of Aβ positivity/negativity by clinical diagnosis, age, and sex. Moderately decreased kidney function to kidney failure was found to influence plasma pTau217 levels.
INTERPRETATION: The prototype pTau217 plasma immunoassay showed high accuracy in reflecting Aβ burden among individuals presenting with cognitive complaints across diverse clinical settings. These findings support its potential implementation into routine clinical practice for early detection of AD, alongside standard clinical and neuropsychologic assessments.
CITATION:
Sayuri Hortsch ; Annunziata Di Domenico ; Niels Borlinghaus ; David Caley ; Laura Kaminioti-Dumont ; Sara Bohn Jeppesen ; Armand González-Escalante ; Craig Ritchie ; Kristian Steen Frederiksen ; Marc Suárez-Calvet (2026): Performance of a fully automated plasma tau phosphorylated at threonine 217 immunoassay to reflect amyloid-beta burden in an unselected cohort representative of clinical practice. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100534
SCREENING FOR ALZHEIMER’S DISEASE IN THE COMMUNITY USING AN AI-DRIVEN SCREENING PLATFORM: DESIGN OF THE PREDICTOM STUDY
Anna-Katharine Brem, Zunera Khan, Jonas Radermacher, Kostas Georgiadis, Ioulietta Lazarou, Margarita Grammatikopoulou, Ellie Pickering, Johanna Mitterreiter, Jon Arild Aakre, Nicholas J. Ashton, Miguel Baquero, Maria Beser-Robles, Claire Braboszcz, Sigurd Brandt, James Brown, Federica Cacciamani, Sarah Campill, Christopher Collins, Pushkar Deshpande, Ana Diaz, Stanley Durrleman, Sebastiaan Engelborghs, Laura Ferré-González, Giovani B. Frisoni, Martha Therese Gjestsen, Dianne Gove, Lee Honigberg, Bin Huang, Anett Hudak, Sandeep Kaushik, Tamas Letoha, Gaby Marquardt, Augusto J. Mendes, Matthias Müllenborn, Lucas Paletta, Nuno Pedrosa de Barros, Martin Pszeida, Audun Osland Vik-Mo, Hossein Rostamipour, Robert Perneczky, Boris-Stephan Rauchmann, Silvia Russegger, Timo Schirmer, Amied Shadmaan, Ana Beatriz Solana, Aureli Soria-Frisch, Paulina Tegethoff, Annemie Ribbens, Sara De Witte, Mark van der Giezen, Spiros Nikolopoulos, Anne Corbett, Holger Fröhlich, Dag Aarsland, the PREDICTOM Consortium
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryBACKGROUND: Recent developments in physiological, imaging and digital biomarkers combined with the approval of new disease-modifying drugs against Alzheimer’s disease (AD) and diagnostic blood tests provide an opportunity to shift the first diagnostic steps to the home-setting. While these novel biomarkers enable scalable screening and earlier detection and treatment of AD, they require an evaluation of their accuracy, feasibility, and safety in primary care and the community setting.
OBJECTIVES: The aim of PREDICTOM is to develop and test the accuracy of an artificial intelligence (AI) driven screening platform for the risk assessment and early detection of AD to extend the clinical pathway to home-based screening using established and novel biomarkers.
DESIGN/SETTING: PREDICTOM is a European (Norway, UK, Belgium, France, Switzerland, Germany, Spain) observational, prospective cohort study using a cloud-based platform that stores a digitalised journey for each participant and provides a collection of artificial-intelligence (AI) algorithms and tools for risk assessment and early diagnosis and prognosis.
PARTICIPANTS: Cohort 1 consists of 4000 adults aged 50 years or older at risk of developing AD. Cohort 2 consists of 615 participants selected from Cohort 1 based on estimates indicating high (N = 415) or low (N = 200) risk of AD. Data from existing cohorts will guide the analytic strategy of the study.
MEASUREMENTS: Cohort 1 will undergo home-based assessments (Level 1), Cohort 2 will undergo in-clinic assessments (Levels 2 and 3). Level 1 includes at-home screening, collecting digital and physiological data (questionnaires, cognition, hearing, eye-tracking) and biofluids (capillary blood via finger-stick and saliva) for biomarker analysis. Level 2 comprises a more complex biomarker collection, most of which can be completed in primary care, including EEG, MRI, venous blood, microbiome from stool, cognition, hearing, and eye-tracking. Level 3 includes a diagnostic evaluation to confirm or rule out AD pathology using established biomarkers (cerebrospinal fluid, or amyloid PET).
CONCLUSIONS: PREDICTOM will develop AI-driven algorithms for the early detection of AD using biomarkers that can be collected at home or in the community care setting, and evaluate their integration into a well-defined and comprehensive clinical pathway.
CITATION:
Anna-Katharine Brem ; Zunera Khan ; Jonas Radermacher ; Kostas Georgiadis ; Ioulietta Lazarou ; Margarita Grammatikopoulou ; Ellie Pickering ; Johanna Mitterreiter ; Jon Arild Aakre ; Nicholas J. Ashton ; Miguel Baquero ; Maria Beser-Robles ; Claire Braboszcz ; Sigurd Brandt ; James Brown ; Federica Cacciamani ; Sarah Campill ; Christopher Collins ; Pushkar Deshpande ; Ana Diaz ; Stanley Durrleman ; Sebastiaan Engelborghs ; Laura Ferré-González ; Giovani B. Frisoni ; Martha Therese Gjestsen ; Dianne Gove ; Lee Honigberg ; Bin Huang ; Anett Hudak ; Sandeep Kaushik ; Tamas Letoha ; Gaby Marquardt ; Augusto J. Mendes ; Matthias Müllenborn ; Lucas Paletta ; Nuno Pedrosa de Barros ; Martin Pszeida ; Audun Osland Vik-Mo ; Hossein Rostamipour ; Robert Perneczky ; Boris-Stephan Rauchmann ; Silvia Russegger ; Timo Schirmer ; Amied Shadmaan ; Ana Beatriz Solana ; Aureli Soria-Frisch ; Paulina Tegethoff ; Annemie Ribbens ; Sara De Witte ; Mark van der Giezen ; Spiros Nikolopoulos ; Anne Corbett ; Holger Fröhlich ; Dag Aarsland ; the PREDICTOM Consortium (2025): Screening for Alzheimer’s disease in the community using an AI-driven screening platform: design of the PREDICTOM study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100545
RIGHT-LATERALIZED CEREBELLAR CORTICAL THICKENING IS ASSOCIATED WITH MILD BEHAVIORAL IMPAIRMENT IN MILD COGNITIVE IMPAIRMENT
Sohee Kim, Young-Chul Jung, Eosu Kim, Keun You Kim, for the Alzheimer\'s Disease Neuroimaging Initiative
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryBACKGROUND: Mild Behavioral Impairment (MBI) reflects later-life emergence of persistent neuropsychiatric symptoms and is increasingly recognized as an early manifestation of neurodegenerative disease, yet cerebellar correlates remain underexplored. We tested whether cerebellar morphometry is associated with incident MBI in mild cognitive impairment (MCI).
METHODS: Using longitudinal Alzheimer’s Disease Neuroimaging Initiative data, MBI was derived from Neuropsychiatric Inventory/ Neuropsychiatric Inventory-Questionnaire items mapped to five diagnostic domains and defined as new symptoms persisting for ≥2 consecutive visits after a symptom-free baseline. Of 530 MCI participants without baseline symptoms, 181 who developed MBI were matched 1:1 to controls by age, sex, and education. DeepCERES quantified lobular cerebellar cortical thickness and asymmetry from 3T T1-weighted MRI. We used logistic regression with false discovery rate correction and conducted domain-specific analyses (affective dysregulation, impulse dyscontrol, decreased motivation).
RESULTS: MBI cases had lower Mini Mental State Examination scores and higher dementia conversion than controls. Greater thickness in right cerebellar lobules IV (OR 1.215), V (OR 1.122), and VIIIB (OR 1.169), and greater asymmetry in right lobule V (OR 1.035), were associated with incident MBI. Affective dysregulation showed the strongest, largely right-lateralized associations and greater interhemispheric asymmetry. Main results were unchanged after separate sensitivity adjustments for Mini Mental State Examination scores and for index-visit psychiatric medication use.
CONCLUSION: Incident MBI in MCI is linked to right-lateralized cerebellar cortical thickening and asymmetry, most prominently for affective dysregulation. These patterns may reflect early compensatory and/or neuroinflammatory processes within cerebello–cortical circuits relevant to affect regulation.
CITATION:
Sohee Kim ; Young-Chul Jung ; Eosu Kim ; Keun You Kim ; for the Alzheimer's Disease Neuroimaging Initiative (2025): Right-lateralized cerebellar cortical thickening is associated with mild behavioral impairment in mild cognitive impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100540
VISUOSPATIAL MEMORY DEFICIT, PLASMA P-TAU217, AND AΒ42/AΒ40 RATIO ENHANCE SENSITIVITY TO IDENTIFY AΒ PET POSITIVITY IN INDIVIDUALS WITH SCD
Qinjie Li, Lin Huang, Ying Wang, Yihui Guan, Fang Xie, Qihao Guo
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryINTRODUCTION: We hypothesize that specific cognitive assessments and plasma biomarkers may exhibit heightened sensitivity during the stage of subjective cognitive decline (SCD). The integration of these plasma biomarkers and cognitive assessments could enhance the ability to predict beta-amyloid (Aβ) pathology in individuals with SCD.
METHODS: A total of 231 participants, including 74 normal controls (NC) and 157 SCD, underwent Aβ and tau PET scans and blood testing for Aβ40, Aβ42, p-tau181, p-tau217, NfL, and GFAP. Cognitive assessments, plasma biomarkers, tau PET SUVr, and demographics were compared between Aβ+ and Aβ− groups within NC and SCD. The least absolute shrinkage and selection operator (LASSO) and logistic regression were employed to perform variable selection and develop predictive models.
RESULTS: We observed significantly worse global cognition, visuospatial memory performance, executive function, and metamemory, as well as higher tau PET SUVr, elevated levels of p-tau217, p-tau181, and GFAP, and lower Aβ42/Aβ40 ratios in SCD Aβ+ compared to SCD Aβ-. The model incorporating BVMT-LD and p-tau217 achieved a slightly higher AUC than the model using p-tau217 and Aβ42/Aβ40 (0.94 vs. 0.93). Partial correlation analyses indicated that both auditory verbal memory (AVLT-LD) and visuospatial memory (BVMT-LD) were significantly negatively associated with p-tau217, whereas only AVLT-LD demonstrated a significant negative association with tau pathology severity.
CONCLUSION: Visuospatial memory deficit and plasma p-tau217 are powerful biomarkers for identifying Aβ+ in SCD. Auditory verbal memory links to tau pathology severity, while visuospatial memory is more sensitive to Aβ deposition, supporting early intervention to prevent AD progression.
CITATION:
Qinjie Li ; Lin Huang ; Ying Wang ; Yihui Guan ; Fang Xie ; Qihao Guo (2026): Visuospatial memory deficit, plasma p-tau217, and Aβ42/Aβ40 ratio enhance sensitivity to identify Aβ PET positivity in individuals with SCD. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100525
NEURONAL AUTOANTIBODIES IN NEURODEGENERATIVE DEMENTIA: FROM EVIDENCE TO CLINICAL FRAMEWORK
Heya Luan, Xiaodong Han, Chang Xu, Aidi Shan, Xin Wang, Shaoqi Li, Qi Yao, Tong Cui, Jinxuan Guo, Boye Wen, Yao Sun, Chuqiao Li, Qingyuan Sun, Cuibai Wei
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryNeuronal autoantibodies, including against neuronal surface receptors or intracellular antigens, are established pathogenic mediators and therapeutic targets in autoimmune encephalitis (AIE) and paraneoplastic neurological syndromes (PNS). These antibodies are now increasingly reported in patients with clinically diagnosed neurodegenerative dementia, prompting re-evaluation of a neurodegenerative etiology. Within neurodegenerative trajectories, whether such antibodies act as pathogenic drivers, non-causal markers, or immune modulators remains unresolved, and heterogeneous cohorts, assays, and endpoints limit inference and clinical translation. This review integrates current research at the intersection of autoimmunity and neurodegeneration and highlights accumulating evidence for a biological continuum. This model suggests that antibody-mediated mechanisms may extend beyond acute inflammation, with sustained exposure contributing to time-dependent neurodegeneration. To facilitate clinical translation, we advance a standardized diagnostic workflow comprising three sequential stages: (i) a pretest-probability triage that defines high-risk constellations prompting antibody testing, stratifies patients accordingly; (ii) a specimen-and-assay pathway for standardized testing workflow and structured interpretation of results; and (iii) post-test integrated analysis to adjudicate pathogenic relevance based on phenotype-antibody concordance. By bridging observational research to clinical decision-making, the framework supports identification of an immunologically modulated neurodegenerative subtype with potential for therapeutic intervention, while reducing false positives and avoiding non-essential immunotherapy in low-probability contexts.
CITATION:
Heya Luan ; Xiaodong Han ; Chang Xu ; Aidi Shan ; Xin Wang ; Shaoqi Li ; Qi Yao ; Tong Cui ; Jinxuan Guo ; Boye Wen ; Yao Sun ; Chuqiao Li ; Qingyuan Sun ; Cuibai Wei (2026): Neuronal autoantibodies in neurodegenerative dementia: From evidence to clinical framework. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100515
INTEGRATIVE SMR PRIORITIZES OXIDATIVE STRESS–RELATED REGULATORY GENES FOR ALZHEIMER’S DISEASE WITH BRAIN-TISSUE VALIDATION
Liu Wu, Yu-Ting Dong, Xin Mu, Xiao Luo, Ze-Jun Chen
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryOxidative stress (OS) plays a critical role in the pathogenesis of Alzheimer’s disease (AD), yet its genetic and epigenetic regulatory mechanisms remain unclear. In this study, we applied a three-step summary-based Mendelian randomization (SMR) framework to integrate Alzheimer’s disease (AD) GWAS summary statistics with peripheral-blood eQTL and mQTL datasets, and further evaluated brain-tissue relevance using GTEx v8 and AMP-AD resources. Across the three-step SMR analyses, we prioritized multiple OS-related candidate genes (e.g., CRLS1, PRKAA1, CYP2E1, GPX1, and APP) associated with AD risk, and brain-tissue analyses further highlighted KEAP1, SIRT1, and PRDX5 as region-relevant signals. Functional enrichment analyses highlighted critical pathways such as "Nrf2-mediated antioxidant response" and "PI3K-AKT signaling," emphasizing the roles of oxidative stress, mitochondrial function, and neuroinflammation in AD. Novel regulatory mechanisms were uncovered at methylation sites (e.g., cg20211653 associated with ABCA1), linking epigenetic regulation to transcriptional mechanisms and providing candidates for brain-tissue follow-up. This study provides new insights into the molecular underpinnings of AD, bridging genetic variation, epigenetic regulation, and transcription, and identifies potential therapeutic targets for mitigating oxidative damage and neurodegeneration.
CITATION:
Liu Wu ; Yu-Ting Dong ; Xin Mu ; Xiao Luo ; Ze-Jun Chen (2026): Integrative SMR prioritizes oxidative stress–related regulatory genes for Alzheimer’s disease with brain-tissue validation. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100535
LIVING ARRANGEMENTS AND COGNITIVE RESILIENCE IN AGING: UNRAVELING DISTINCT PATHWAYS THROUGH PLASMA BIOMARKERS
Yuanyuan Peng, Heqianxi Dong, Yu Luo, Wen Zhou, Lu Liu, Ming Chen, Na Liu, Jiwen Che, Feifei Hu, Yifeng Cheng, Xinyan Xie, Yan Zeng
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryBACKGROUND: Global aging and changing family structures necessitate identifying modifiable factors for cognitive health. While social isolation is a known risk, the protective role of specific living arrangements and their interplay with neurobiology is unclear.
OBJECTIVES: This study aimed to: (1) examine the longitudinal association between living arrangements and cognitive function in older adults, and (2) investigate the potential moderating roles of plasma Alzheimer’s disease (AD) biomarkers in this relationship.
METHODS: Using data from the Hubei Memory and Aging Cohort Study, we followed 3403 older adults aged 65 years and above with different living arrangements. Participants underwent standardized cognitive assessments and plasma biomarker measurements, including amyloid-beta (Abeta) 40, Abeta 42, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau) 181, and p-tau 217. Linear mixed-effects models were employed to analyze cognitive trajectories.
RESULTS: Compared to older adults living separately from their families, those in two specific living arrangements, living with a spouse only or in multigenerational living, demonstrated significantly better cognitive performance across multiple domains. These protective associations proved robust even after comprehensive adjustment for plasma AD biomarkers. Importantly, we found that higher plasma GFAP levels significantly attenuated the cognitive benefits conferred by favorable living arrangements. In a separate, distinct pathway, higher plasma Abeta40 levels were independently associated with better-preserved language function over time.
CONCLUSIONS: Favorable living arrangements may benefit cognitive health through pathways independent of typical AD pathology. Incorporating living arrangements and plasma biomarkers, particularly GFAP, could enhance risk assessment and targeted interventions for cognitive decline in older adults.
CITATION:
Yuanyuan Peng ; Heqianxi Dong ; Yu Luo ; Wen Zhou ; Lu Liu ; Ming Chen ; Na Liu ; Jiwen Che ; Feifei Hu ; Yifeng Cheng ; Xinyan Xie ; Yan Zeng (2026): Living arrangements and cognitive resilience in aging: unraveling distinct pathways through plasma biomarkers. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100536
MODIFIABLE LIFESTYLE FACTORS FOR DEMENTIA RISK IN AN ONLINE COHORT ASSESSED BY THE MOCA COGNITIVE HEALTH ASSESSMENT INDEX (MOCA-CHAI)
Laura Klaming, Hans-Aloys Wischmann, Murray Gillies, Ziad Nasreddine
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryBACKGROUND: The growing prevalence of dementia highlights the need for a risk assessment tool that is accessible, facilitates the identification of at-risk individuals, and provides evidence-based guidance on how to reduce dementia risk.
OBJECTIVES: We developed, deployed, and evaluated the MoCA-CHAI, a self-administered, online dementia risk assessment for the general public. We provide a brief overview of its development, the self-enrolled population that has completed it, and a preliminary evaluation of its predictive performance.
METHODS: Drawing on the 2024 Lancet report, we developed the MoCA-CHAI translating the 14 identified risk factors into a questionnaire. We used the MoCA XpressO as a measure of cognitive impairment and a proxy measure for the probability of having or developing dementia.
FINDINGS: The MoCA-CHAI was completed by 3886 people. Based on their XpressO score, 11.3% showed a high probability of cognitive impairment. Using a logistic regression analysis, we found that each 1-point increase in MoCA-CHAI score decreases the odds of having cognitive impairment by 1%. Physical inactivity and exposure to air pollution are the most prevalent risk factors across the lifespan. Depression is more prevalent in young adults, while high cholesterol, hypertension, diabetes, and excessive alcohol consumption are more prevalent in middle-aged and older adults.
CONCLUSIONS: These findings demonstrate that the MoCA-CHAI provides insight into modifiable lifestyle factors and dementia risk. Differences in prevalences of risk factors indicate that prevention strategies need to be tailored to age-specific risk profiles. The MoCA-CHAI may help identify at-risk individuals who could benefit from targeted prevention and monitoring.
CITATION:
Laura Klaming ; Hans-Aloys Wischmann ; Murray Gillies ; Ziad Nasreddine (2025): Modifiable lifestyle factors for dementia risk in an online cohort assessed by the MoCA Cognitive Health Assessment Index (MoCA-CHAI). The Journal of Prevention of Alzheimer’s Disease (JPAD). Laura Klaming
LATE-LIFE BODY MASS INDEX AND AMYLOID INTERACTION ON COGNITIVE DECLINE IN UNIMPAIRED OLDER ADULTS
Wai-Ying Wendy Yau, Rema Raman, Jasmeer Chhatwal, Jeremy J. Pruzin, Zahra Shirzadi, Neelum Aggarwal, Adam M. Brickman, Petrice M. Cogswell, Jonathan Graff-Radford, Jay J. Pillai, Prashanthi Vemuri, Michael S. Rafii, Roy Yaari, Paul Aisen, Reisa Sperling, The A4 and LEARN Study Teams
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryBACKGROUND: The late-life “obesity paradox” of reduced Alzheimer’s disease (AD) risk is postulated to be driven by underlying preclinical/prodromal pathology. However, few studies have directly examined the joint associations of BMI and amyloid pathology with cognitive decline, especially in individuals with preclinical AD targeted in prevention trials.
OBJECTIVE: To determine whether late-life BMI and amyloid pathology have independent or interactive associations with cognition in clinically unimpaired older adults.
DESIGN: Secondary analyses of A4 randomized clinical trial and the companion observational LEARN Study (median follow-up 4.7 years).
SETTING: Multicenter across 67 sites in US, Canada, Australia, and Japan.
PARTICIPANTS: We included 1663 participants (Placebo n = 582, Solanezumab n = 563, LEARN n = 518) who were baseline cognitively unimpaired and medically stable, mean age 71.5 ± 4.7 years, 60% women.
MEASUREMENTS: BMI and global amyloid burden [Florbetapir PET] were measured at baseline. Cognition was measured longitudinally using Preclinical Alzheimer Cognitive Composite.
RESULTS: Higher BMI and amyloid burden were independently associated with worse baseline cognition. Longitudinally, a BMI*Amyloid*Time interaction emerged: lower/normal BMI was associated with more favorable cognitive trajectory at low amyloid levels, but with faster cognitive decline when amyloid was substantially elevated.
CONCLUSIONS: Our cross-sectional findings support a negative association between obesity and cognitive aging up to late-life. Longitudinally, we observed an “obesity paradox”, where higher/obese BMI was associated with more favorable cognitive trajectories in the presence of advanced amyloid pathology. Together, our findings suggest that future trials targeting obesity to slow late-life cognitive decline may benefit from preferentially enrolling younger individuals or those without substantial amyloid accumulation.
CITATION:
Wai-Ying Wendy Yau ; Rema Raman ; Jasmeer Chhatwal ; Jeremy J. Pruzin ; Zahra Shirzadi ; Neelum Aggarwal ; Adam M. Brickman ; Petrice M. Cogswell ; Jonathan Graff-Radford ; Jay J. Pillai ; Prashanthi Vemuri ; Michael S. Rafii ; Roy Yaari ; Paul Aisen ; Reisa Sperling ; The A4 and LEARN Study Teams (2025): Late-life body mass index and amyloid interaction on cognitive decline in unimpaired older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100543
VALIDATION OF A NOVEL COGNITIVE-FUNCTIONAL OUTCOME MEASURE OPTIMIZED FOR EARLY ALZHEIMER’S DISEASE: EVIDENCE FROM THE VIVA-MIND TRIAL
Jasmin A. Duehring, Diane M. Jacobs, David P. Salmon, Andrew J. MacKelfresh, Carolyn Revta, Antje Meyer, Michael Schaeffer, Sylvia Schell-Mader, Tanja Wassmann, Christine Wenzkowski, Howard H. Feldman, Steven D. Edland, ADCS VIVA-MIND Study Group
J Prev Alz Dis 2026;5(13)
Show summaryHide summaryBACKGROUND: Cognitive-functional composite measures are increasingly used as primary efficacy endpoints in early Alzheimer’s disease (AD) trials, where greater sensitivity to decline can improve trial efficiency and reduce sample size requirements.
OBJECTIVES: To compare sensitivity to decline of the Cognitive Functional Component 2 (CFC2), a novel cognitive-functional composite measure described by Raghavan et al. (2013), against the Clinical Dementia Rating - Sum of Boxes (CDR-SB) and other standard cognitive and functional outcomes including MMSE, FAQ, ADAS Cog 13 and ADCOMS using prospective randomized clinical trial data.
DESIGN: The VIVA-MIND trial was a phase 2A/2B randomized controlled trial investigating the safety and efficacy of varoglutamstat in patients with mild cognitive impairment and mild dementia due to AD.
SETTING: The VIVA-MIND trial was conducted between 2021–2024. It was prematurely terminated in mid-2024 by the study sponsor.
PARTICIPANTS: This secondary analysis uses data from 98 participants in the modified intention-to-treat population from the VIVA-MIND trial with complete neuropsychological test data.
MEASUREMENTS: Standard power calculations informed by parameters estimated from linear mixed-effects models were used to determine the relative efficiency of outcome measures.
RESULTS: The CFC2 was more sensitive to decline than the CDR-SB in this population. Use of the CFC2 would yield a 15% reduction in required sample size relative to the CDR-SB. Application of an optimal weighting scheme further improved the sensitivity of the CFC2.
CONCLUSIONS: Practically significant differences in the efficiency of clinical trials in early AD may be realized by the choice of clinical outcome measure and weighting scheme. Although further verification is needed, we replicate a previous finding that the CFC2 may outperform the CDR-SB in the early AD population.
CITATION:
Jasmin A. Duehring ; Diane M. Jacobs ; David P. Salmon ; Andrew J. MacKelfresh ; Carolyn Revta ; Antje Meyer ; Michael Schaeffer ; Sylvia Schell-Mader ; Tanja Wassmann ; Christine Wenzkowski ; Howard H. Feldman ; Steven D. Edland ; ADCS VIVA-MIND Study Group (2026): Validation of a novel cognitive-functional outcome measure optimized for early Alzheimer’s Disease: Evidence from the VIVA-MIND trial. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2026.100531
LETTER TO THE EDITOR: DONANEMAB THERAPY IN ALZHEIMER’S DISEASE WITH MILD COGNITIVE IMPAIRMENT: CONVERGENT AMYLOID, TAU, AND PLASMA BIOMARKER NORMALIZATION WITH COGNITIVE IMPROVEMENT
Limoran Tang, Yun Xu, Hui Zhao
J Prev Alz Dis 2026;5(13)
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CITATION:
Limoran Tang ; Yun Xu ; Hui Zhao (): Letter to the Editor: Donanemab therapy in Alzheimer’s disease with mild cognitive impairment: Convergent amyloid, tau, and plasma biomarker normalization with cognitive improvement. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100533