Ahead of print articles
CORRIGENDUM TO “LECANEMAB FOR TREATMENT OF INDIVIDUALS WITH EARLY ALZHEIMER’S DISEASE (AD) WHO ARE APOLIPOPROTEIN E Ε4 (APOE Ε4) NON-CARRIERS OR HETEROZYGOTES” [THE JOURNAL OF PREVENTION OF ALZHEIMER\'S DISEASE (2026) 100507]
Richard Perry, Christopher Kipps, Maria Eugenia Soto Martín, Marco Bozzali, Giancarlo Logroscino, Sarah Trafford, Shobha Dhadda, Michio Kanekiyo, Amanda Goodwin, Mark Hodgkinson, Steven Hersch, Michael Irizarry, Lynn Kramer, Lutz Froelich
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CITATION:
Richard Perry ; Christopher Kipps ; Maria Eugenia Soto Martín ; Marco Bozzali ; Giancarlo Logroscino ; Sarah Trafford ; Shobha Dhadda ; Michio Kanekiyo ; Amanda Goodwin ; Mark Hodgkinson ; Steven Hersch ; Michael Irizarry ; Lynn Kramer ; Lutz Froelich (2026): Corrigendum to “Lecanemab for treatment of individuals with early Alzheimer’s Disease (AD) who are apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes” [The Journal of Prevention of Alzheimer's Disease (2026) 100507]. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100527
HEALTHY LIFESTYLE AND ALZHEIMER’S DISEASE IN INDIVIDUALS WITH HYPERLIPIDEMIA: A PROSPECTIVE COHORT STUDY
Danyang Sun, Linling Yu, Chenqi Liao, Yuzhong Xu, Wei Liu, Xiong Wang
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BACKGROUND: Whether healthy lifestyle behaviors are associated with Alzheimer’s disease (AD) risk among individuals with hyperlipidemia remains unclear.
METHODS: We analyzed 241,642 dementia-free participants from the UK Biobank. A weighted lifestyle score (0–7) was derived from seven factors and categorized into five tiers. Hyperlipidemia was defined as lipid-lowering medication use or LDL-cholesterol ≥ 4.0 mmol/L. Cox regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs).
RESULTS: Over a median follow-up of 14.5 years, 1728 AD cases occurred, including 977 cases among 104,082 individuals with hyperlipidemia. Compared with the intermediate tier, unhealthy lifestyle was associated with elevated AD risk (HR: 1.17; 95% CI: 1.02–1.35), while healtshy and very healthy tiers were associated with progressively lower risk (HR=0.85 and 0.74, respectively). These associations were evident among individuals with hyperlipidemia, but not statistically significant among those without hyperlipidemia.
CONCLUSIONS: Healthy lifestyle patterns were associated with lower AD risk among individuals with hyperlipidemia, with greater risk reductions observed for healthier lifestyle tiers.
CITATION:
Danyang Sun ; Linling Yu ; Chenqi Liao ; Yuzhong Xu ; Wei Liu ; Xiong Wang (2026): Healthy lifestyle and Alzheimer’s disease in individuals with hyperlipidemia: A prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100520
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
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BACKGROUND: 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
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
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BACKGROUND: 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
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
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Oxidative 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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
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
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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
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
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BACKGROUND: 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
SOCIODEMOGRAPHIC DIFFERENCES IN DEMENTIA PREVENTION KNOWLEDGE IN GERMANY: IMPLICATIONS FOR TARGETED HEALTH COMMUNICATION
Pauline Albus, Ann-Kristin Folkerts, Josef Kessler, Sebastian Köhler, Elke Kalbe
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BACKGROUND: 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
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
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INTRODUCTION: 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
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
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Amyloid 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
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
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BACKGROUND: 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
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
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Neuronal 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
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
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INTRODUCTION: 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
EDITORIAL: REMOTE OUTCOME MEASURES IN ALZHEIMER\'S DISEASE CLINICAL TRIALS: A CALL TO ACTION
Gustavo A. Jimenez-Maggiora
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CITATION:
Gustavo A. Jimenez-Maggiora (2026): Editorial: Remote outcome measures in Alzheimer's disease clinical trials: A call to action. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100528
PREDICTING COGNITIVE DECLINE: COMPARATIVE ANALYSIS OF ANU-ADRI, CAIDE, COGDRISK, LIBRA, LIBRA2, UKBDRS AND LANCET BASED DEMENTIA RISK SCORES IN THE HUNT STUDY
Josephine Stubs, Geir Selbæk, Bjørn Heine Strand, Gill Livingston, Kaarin J. Anstey, Kay Deckers, Mika Kivimäki, Steinar Krokstad, Fiona E. Mathews, Ellen Melbye Langballe
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OBJECTIVE: To evaluate and compare the predictive value of eight dementia risk scores for late-life cognitive function and cognitive decline; ANU-ADRI, CAIDE, CogDrisk, LIBRA, LIBRA2, UKBDRS(-APOE), and a Lancet commission-based risk score.
METHODS: Using Norwegian Trøndelag Health Study (HUNT) data, we calculated risk scores from lifestyle and health data of 7221 dementia-free participants (mean age: 76.8 years, 54.1% female) collected in HUNT3 (2006–2008). Cognitive function was assessed using the Montreal Cognitive Assessment scale (MoCA) 11 years later in HUNT4 70+, and reassessed in 4716 participants 4 years thereafter. Associations between continuous risk scores or risk score tertiles, cognition and cognitive decline were examined using linear mixed-effects models. Logistic regression models were used to test associations between risk scores and a ≥ 3-point decline in MoCA scores.
RESULTS: All risk scores were significantly associated with cognitive function and cognitive decline. Associations with cognitive function ranged from UKBDRS β per 1SD=-1.61(95%CI:-1.72,-1.51) to CAIDE (β=-0.74;95%CI:-0.82,-0.67), and with yearly cognitive decline from Lancet (β=-0.23;95%CI:-0.27,-0.18) to CAIDE (β=-0.04;95%CI:-0.07,-0.02). High-low risk group differences in cognitive function were largest for CogDrisk (β=-3.04;95%CI:-3.27,-2.81), LIBRA (β=-3.04;95%CI:-3.27,-2.80) and lowest for CAIDE (β=-1.65;95%CI:-1.86,-1.44). High-risk groups showed the steepest decline for UKBDRS-APOE (β=-0.43;95%CI:-0.52,-0.34), Lancet (β=-0.39;95%CI:-0.48,-0.30), and LIBRA (β=-0.38;95%CI:-0.47,-0.28). All scores predicted ≥3-point decline modestly: AUCs were highest for UKBDRS (AUC=0.61;95%CI:0.60,0.63), UKBDRS-APOE (0.61;95%CI:0.60,0.63), CogDrisk (0.60;95%CI:0.58,0.62), and Lancet (0.60;95%CI:0.58,0.61), but none outperformed a model including age and education alone (0.61;95%CI:0.60,0.63).
CONCLUSION: Risk scores captured meaningful gradients in cognition and decline but offered limited discriminatory accuracy beyond demographics, supporting their use for prevention-oriented risk profiling rather than prediction.
CITATION:
Josephine Stubs ; Geir Selbæk ; Bjørn Heine Strand ; Gill Livingston ; Kaarin J. Anstey ; Kay Deckers ; Mika Kivimäki ; Steinar Krokstad ; Fiona E. Mathews ; Ellen Melbye Langballe (2026): Predicting cognitive decline: Comparative analysis of ANU-ADRI, CAIDE, CogDrisk, LIBRA, LIBRA2, UKBDRS and Lancet based dementia risk scores in the HUNT study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100524
VASCULAR STIFFNESS PREDICTS PLASMA MARKERS OF NEURODEGENERATION AMONG OLDER AFRICAN AMERICANS
Miray Budak, Kevin S. Heffernan, Victoria Paruzel, Soodeh Moallemian, Bernadette A. Fausto, Nicholas Ashton, Henrik Zetterberg, Fanny M. Elahi, Mark A. Gluck
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BACKGROUND: Vascular health is a critical and potentially modifiable determinant of Alzheimer’s disease (AD) risk, yet its contribution to early neurodegenerative processes remains incompletely understood, particularly among African Americans, who experience a disproportionate AD burden. Estimated pulse wave velocity (ePWV), derived from age and blood pressure, provides a scalable index of vascular stiffness.
OBJECTIVES: To examine associations between vascular stiffness and plasma biomarkers of AD-related neurodegeneration in older African Americans.
DESIGN: Cross-sectional observational study.
SETTING: Community-based aging cohort study conducted at an academic research center.
PARTICIPANTS: A total of 145 cognitively unimpaired older African Americans (mean age=71.18±6.83 years; 110 women).
MEASUREMENTS: ePWV was calculated using validated equations based on age and blood pressure. Plasma biomarkers included phosphorylated tau217 (p-tau217; N=145), phosphorylated tau231 (p-tau231; N=126), glial fibrillary acidic protein (GFAP; N=126), neurofilament light chain (NfL; N=126), and amyloid-β42/40 ratio (Aβ42/40; N=126). Multivariable regression models adjusted for sex, education, pulse pressure, waist-to-hip ratio, global cognition, and hypertension status.
RESULTS: Higher ePWV was significantly associated with higher plasma concentrations of p-tau217 (β=0.34, p=.006), GFAP (β=0.55, p<.001), and NfL (β=0.52, p<.001), but not with p-tau231 and Aβ42/40 (p>.05).
CONCLUSIONS: Greater vascular stiffness, indexed by elevated ePWV, was associated with circulating markers of tau-related neurodegeneration, astrocytic activation, and axonal injury in cognitively unimpaired older African Americans. The absence of association with p-tau231 and Aβ42/40 suggests preferential effects on neurovascular damage and later tau-related processes, but no primary effect on biomarkers related to Aβ pathology, still highlighting vascular health as a modifiable target for AD prevention.
CITATION:
Miray Budak ; Kevin S. Heffernan ; Victoria Paruzel ; Soodeh Moallemian ; Bernadette A. Fausto ; Nicholas Ashton ; Henrik Zetterberg ; Fanny M. Elahi ; Mark A. Gluck (2026): Vascular stiffness predicts plasma markers of neurodegeneration among older African Americans. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100523
LIFESTYLE FACTORS AND DNA METHYLATION-BASED AGING CLOCKS: CROSS-SECTIONAL AND LONGITUDINAL ASSOCIATIONS IN THE SINGAPORE DIET AND HEALTHY AGING COHORT
Jiatong Shan, Jian Hua Tay, Kaisy Xinhong Ye, Jiuyu Guo, Luwen Cao, Yan Zeng, Tih-Shih Lee, Kua Ee Heok, Brian K. Kennedy, Andrea B. Maier, Lei Feng
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BACKGROUND: Lifestyle factors play a critical role in healthy aging, yet their relationships with aging biomarkers remain insufficiently characterized, particularly in Asian populations. This study aimed to examine the cross-sectional and longitudinal associations between 15 modifiable lifestyle factors and two DNA methylation (DNAm) clocks (GrimAge acceleration [AgeDev] and DunedinPACE) in a cohort of older Asian adults.
METHODS: We conducted a cross-sectional analysis of 631 participants (median age 70.0 years; 72.6% female) and a longitudinal analysis of 114 participants (mean follow-up 3.96 years) from the Singapore Diet and Healthy Aging (DaHA) cohort. Lifestyle exposures were assessed using validated self-administered questionnaires. Peripheral blood DNAm profiles were generated using the Illumina MethylationEPIC array. Multivariable linear regression models were applied to evaluate associations between lifestyle factors and DNAm clocks, adjusting for sociodemographic covariates, health status, and immune cell-type proportions.
RESULTS: In cross-sectional analyses, smoking history showed robust positive associations with accelerated epigenetic aging (GrimAge AgeDev: β = 1.45, 95% CI 1.13–1.77, p < 0.0001; DunedinPACE: β = 0.63, 95% CI 0.22–1.05, p = 0.003). Conversely, weekly physical activity was associated with slower aging (GrimAge AgeDev: β = –0.22, 95% CI –0.40 to –0.04, p = 0.02), as was daily engagement in cognitively stimulating activities (GrimAge AgeDev: β = –0.16, 95% CI –0.31 to –0.01, p = 0.04). Weekly feelings of stress were initially associated with greater GrimAge AgeDev, but this relationship was attenuated after full adjustment. No significant longitudinal associations were detected, which may reflect limited statistical power and the stability of long-standing lifestyle behaviors over the follow-up period.
CONCLUSIONS: These findings highlight significant cross-sectional associations between key modifiable lifestyle factors, particularly smoking, physical activity, and cognitive engagement, and epigenetic aging in an older Asian cohort. The results suggest that interventions targeting these behaviors may modulate the pace of biological aging. The absence of significant longitudinal associations underscores the need for larger prospective studies with longer follow-up and continued validation of epigenetic clocks in diverse populations to confirm these relationships over time.
CITATION:
Jiatong Shan ; Jian Hua Tay ; Kaisy Xinhong Ye ; Jiuyu Guo ; Luwen Cao ; Yan Zeng ; Tih-Shih Lee ; Kua Ee Heok ; Brian K. Kennedy ; Andrea B. Maier ; Lei Feng (2026): Lifestyle factors and DNA methylation-based aging clocks: cross-sectional and longitudinal associations in the Singapore diet and healthy aging cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100522
ASSOCIATIONS BETWEEN PLANT-BASED DIETARY PATTERNS AND RISKS OF COGNITIVE IMPAIRMENT AND DEMENTIA: A SYSTEMATIC REVIEW AND DOSE-RESPONSE META-ANALYSIS
Jui-Hsiu Tsai, Tou-Yuan Tsai, Hua Li, Cheng-Yu Wang, Yu-Kang Tu, Huei-Kai Huang, Hsin Ma, Yu-Lin Hsieh, Chuan-Sheng Hung, Shih-Chieh Shao, Eric H Chou, Chin-Lon Lin, Ming-Nan Lin
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BACKGROUND: Evidence remains inconclusive regarding plant-based diets preventing cognitive impairment and dementia, as certain plant-based foods, including refined carbohydrates, sweets, sugar-sweetened beverages, and trans fats, may increase dementia risk.
OBJECTIVES: To quantitatively synthesize prospective cohort studies on associations between adherence to plant-based diets and the risks of cognitive impairment and dementia.
DESIGN: Systematic review and meta-analysis. This study adhered to the PRISMA guidelines and was registered on PROSPERO (No: CRD42024501334).
SETTING: Studies published until December 2025 were systematically identified using AgeLine, CINAHL, Embase, MEDLINE, PsycINFO, Scopus, and Web of Science.
PARTICIPANTS: The study population comprised adults aged ≥ 20 years with no cognitive impairment at baseline.
INTERVENTION: Studies were enrolled if the participants (1) assessed dietary patterns characterized by higher plant-based food consumption and decreased or ceased consumption of animal-based foods or (2) used established dietary indices, including overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI).
MEASUREMENTS: Data extraction, risk of bias assessment, and the GRADE approach for assessing certainty of evidence were performed independently by three reviewers. A random-effects model with restricted maximum likelihood was used to calculate pooled risk ratios and 95% confidence intervals. The dose-response meta-analysis used two-stage dose-response regression.
RESULTS: The meta-analysis based on seven studies (number of participants: 221,380; number of cases of incident cognitive impairment and dementia: 5668) indicated that participants with greater adherence to plant-based diets had significantly lower risks of cognitive impairment and dementia (pooled risk ratio, 0.74; 95% confidence interval, 0.56–0.97; I2 = 92.3%) than those with lower adherence. Dose-response relationships modeled using restricted cubic splines indicated that overall PDI and hPDI were negatively associated with risks of cognitive impairment and dementia, whereas uPDI was significantly positively associated with these risks.
CONCLUSIONS: This meta-analysis suggests that adherence to plant-based diets, particularly those rich in healthful plant foods, may be associated with a lower risk of cognitive impairment and dementia. However, given the residual heterogeneity and the inherent limitations of observational study designs, large randomised controlled trials are warranted to establish causality.
CITATION:
Jui-Hsiu Tsai ; Tou-Yuan Tsai ; Hua Li ; Cheng-Yu Wang ; Yu-Kang Tu ; Huei-Kai Huang ; Hsin Ma ; Yu-Lin Hsieh ; Chuan-Sheng Hung ; Shih-Chieh Shao ; Eric H Chou ; Chin-Lon Lin ; Ming-Nan Lin (2026): Associations between plant-based dietary patterns and risks of cognitive impairment and dementia: A systematic review and dose-response meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100521
LONGITUDINAL SUBCORTICAL VOLUME CHANGES AND THEIR CORRELATIONS WITH MULTIPLE PET AND FLUID BIOMARKERS IN DOMINANTLY INHERITED ALZHEIMER’S DISEASE
IL Han Choo, Hoyoung Park, Brian A. Gordon, Randall J. Bateman, the Dominantly Inherited Alzheimer Network
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BACKGROUND: Alzheimer's disease postmortem studies demonstrate that amyloid plaques and neurofibrillary tangles are present in subcortical regions.
OBJECTIVE: To investigate longitudinal subcortical structural changes in autosomal dominant Alzheimer’s disease in relation to multiple PET and fluid biomarkers.
DESIGN: Dominantly Inherited Alzheimer’s Network (DIAN) Observational study.
SETTING: Multicenter study.
PARTICIPANTS: Participants were identified as mutation-carriers of pathologic variants in presenilin-1, presenilin-2, or amyloid precursor protein and as non-carriers from the same families as the mutation-carriers. They underwent baseline and 2 and more times longitudinal follow-up assessments of multiple biomarkers
MEASUREMENTS: Participants underwent structural MRI, ¹¹C-Pittsburgh Compound B PET, ¹⁸F-fluorodeoxyglucose PET, and CSF and plasma assessments. Rates of biomarker change as a function of estimated years to symptom onset were estimated using multivariate linear mixed-effects models, and longitudinal associations between subcortical atrophy and multiple biomarkers were evaluated.
RESULTS: A total of 601 participants completed one or more clinical evaluations, with up to eight annual visits. Mutation carriers showed significantly greater longitudinal atrophy in the left amygdala, bilateral thalamus, putamen, nucleus accumbens, and hippocampus compared with non-carriers (Bonferroni-corrected p < 0.05). The earliest divergence was observed 13.2 years before the expected symptom onset in the right nucleus accumbens, following amyloid-β (Aβ) accumulation in the right thalamus that began 23.8 years before onset. Among carriers, atrophy in the right thalamus, bilateral putamen, and bilateral nucleus accumbens was significantly associated with region-specific or cortical Aβ accumulation, as well as with CSF Aβ42, Aβ42/Aβ40 ratio, total tau, and phosphorylated tau (Bonferroni-corrected p < 0.05).
CONCLUSIONS: The present findings may provide a unique and well-characterized model for investigating the temporal ordering of Alzheimer’s disease biomarkers.
CITATION:
IL Han Choo ; Hoyoung Park ; Brian A. Gordon ; Randall J. Bateman ; the Dominantly Inherited Alzheimer Network (2026): Longitudinal subcortical volume changes and their correlations with multiple PET and fluid biomarkers in dominantly inherited Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100513
DIAGNOSTIC AND PROGNOSTIC UTILITY OF SERUM Β-SYNUCLEIN IN ALZHEIMER’S DISEASE: A LONGITUDINAL COHORT STUDY
Siqi Xie, Yumei Liang, Ting Yang, Dandan Sheng, Lan Ding, Jianping Jia, Alzheimer’s Disease Neuroimaging Initiative
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BACKGROUND: Serum β-synuclein is an emerging blood-based biomarker for synaptic integrity in Alzheimer’s disease (AD). However, its comparative performance against the established CSF marker neurogranin and its prognostic utility for longitudinal disease progression remain to be fully characterized.
METHOD: We analyzed 475 participants from the Alzheimer’s Disease Neuroimaging Initiative. We compared serum β-synuclein and CSF neurogranin using receiver operating characteristic analysis and Cox proportional hazards models. We also assessed the cross-sectional associations of both biomarkers with cognitive and neuroimaging markers using linear regression. Linear mixed-effects models were applied to determine if baseline serum β-synuclein levels and longitudinal rate of change predicted disease progression. Finally, the trajectory of serum β-synuclein was modeled across the AD continuum.
RESULTS: Serum β-synuclein distinguished clinical AD dementia from controls with high accuracy (AUC = 0.84). Cross-sectionally, it exhibited robust associations with cognitive deficits and neuroimaging markers, comparable to or exceeding those of CSF neurogranin. Higher baseline serum β-synuclein, but not CSF neurogranin, significantly predicted the risk of conversion to dementia (hazard ratio = 1.83). Longitudinally, both elevated baseline levels and faster rates of increase in serum β-synuclein predicted accelerated cognitive decline and neurodegeneration, independent of baseline amyloid or tau pathology. Trajectory analysis revealed that serum β-synuclein levels accelerated significantly over time specifically in individuals with concurrent amyloid and tau pathology.
DISCUSSION: Serum β-synuclein serves as a robust prognostic biomarker for AD, demonstrating diagnostic accuracy for clinical dementia and superior predictive utility for disease conversion compared to CSF neurogranin. Its ability to track synaptic degeneration independent of core proteinopathies highlights its potential as a dynamic outcome measure for monitoring disease progression in clinical trials.
CITATION:
Siqi Xie ; Yumei Liang ; Ting Yang ; Dandan Sheng ; Lan Ding ; Jianping Jia ; Alzheimer’s Disease Neuroimaging Initiative (2026): Diagnostic and prognostic utility of serum β-synuclein in Alzheimer’s disease: a longitudinal cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100514
LETTER TO THE EDITOR: LONG-TERM TREATMENT OF EARLY ALZHEIMER’S DISEASE WITH DONANEMAB
Vincenzo Solfrizzi, Bruno P. Imbimbo
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CITATION:
Vincenzo Solfrizzi ; Bruno P. Imbimbo (2026): Letter to the Editor: Long-term treatment of early Alzheimer’s disease with donanemab. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100512
ASSOCIATION BETWEEN MRI INDICATORS OF THE GLYMPHATIC SYSTEM AND COGNITION IN HIGH-RISK POPULATIONS FOR ALZHEIMER\'S DISEASE
Li Jiang, Ling Zhang, Shu-Xian Wu, Qin-Qin Zhu, Wei Wang, Jia-Wei Gao, Yi Zhu, Shui Tian, Ming Qi
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BACKGROUND: Using the Diffusion Tensor Image Analysis Along the Perivascular Space (ALPS) method and perivascular space (PVS) burden to study glymphatic function in high-risk Alzheimer's disease (AD) populations, this research investigates the correlation between ALPS index and PVS volume with cognitive function respectively.
METHODS: This study enrolled 126 participants, including 21 cognitively unimpaired (CU) individuals, 68 with subjective cognitive decline (SCD), and 37 with mild cognitive impairment (MCI). All participants underwent MRI and cognitive assessments. MRI measures, including the PVS burden and the ALPS index, were compared across SCD, MCI, and CU groups. Additionally, correlations among the ALPS index, PVS burden, and cognitive scales were analyzed.
RESULTS: The PVS in the basal ganglia volume fraction (PVSVF-BG) in patients with MCI was significantly larger than the fraction in CUs (p < 0.05) and a higher PVSVF-BG was associated with poorer performance on the Trail Making Test A (TMTA) (r = 0.29, p < 0.05). Compared with the CU and SCD groups, patients with MCI exhibited a significantly lower ALPS index in both the left (p < 0.05) and right hemispheres (p < 0.001). Lower whole brain ALPS index in patients with MCI was correlated with worse performance in the Auditory Verbal Learning Test(AVLT) (N4, r = 0.33, p < 0.05; N7, r = 0.56, p < 0.001).
CONCLUSIONS: An increased PVS burden and a decreased ALPS index can be observed in the preclinical stage of AD, which may suggest impaired glymphatic system function. These impairments were further correlated with worse cognitive performance in terms of attention in SCD and memory in MCI.
CITATION:
Li Jiang ; Ling Zhang ; Shu-Xian Wu ; Qin-Qin Zhu ; Wei Wang ; Jia-Wei Gao ; Yi Zhu ; Shui Tian ; Ming Qi (2026): Association between MRI indicators of the glymphatic system and cognition in high-risk populations for Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100504
THE ROLE OF LIPIDS IN MEDIATING THE EFFECTS OF IMMUNE CELLS ON ALZHEIMER’S DISEASE RISK: A NETWORK MENDELIAN RANDOMIZATION STUDY
Xinyu Yang, Jingjing Jiang, Wenjing Li, Rui Pan, Yanjie Li
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BACKGROUND: Observational studies have shown associations between immune cells, lipids, and Alzheimer’s disease (AD), but their specific causal relationships and the mediating role of lipids remain unclear.
METHODS: Within a network Mendelian randomization (MR) framework, we first applied two-sample univariable MR to assess the causal effects of immune cells and lipids on AD. Then, multivariable MR was used in mediation analyses to determine whether lipids mediate the effects of immune cells on AD. Finally, reverse MR analyses were performed to minimize potential bias from reverse causation. The inverse variance weighted method was used as the primary estimator.
RESULTS: The analysis revealed that elevated levels of CD33 on CD33dim HLA DR+ CD11b+ and CD33 on CD33dim HLA DR+ CD11b- were associated with an increased risk of AD. Mediation analysis further indicated that polyunsaturated fatty acids are protective lipid metabolites for AD and partially mediate the effects of the aforementioned immune cells on AD, with mediation proportions of 3.70 % and 3.67 %, respectively.
CONCLUSION: This study provides new insights into how immune cells may influence AD pathogenesis through lipid metabolism. It also offers a theoretical basis and potential direction for developing immune–lipid-based strategies for AD prevention and intervention.
CITATION:
Xinyu Yang ; Jingjing Jiang ; Wenjing Li ; Rui Pan ; Yanjie Li (2026): The role of lipids in mediating the effects of immune cells on Alzheimer’s disease risk: A network Mendelian randomization study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100509
LETTER TO THE EDITOR : LONG-TERM EXTENSION DATA DO NOT ROBUSTLY SUPPORT CLINICAL DISEASE COURSE MODIFICATION WITH DONANEMAB
Jemma Hazan, Kathy Y. Liu, Robert Howard
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CITATION:
Jemma Hazan ; Kathy Y. Liu ; Robert Howard (2026): Letter to the Editor: Long-term extension data do not robustly support clinical disease course modification with donanemab. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100511
ESTIMATED PREVALENCE OF UNDERDIAGNOSED DEMENTIA IN A MULTIETHNIC COMMUNITY-BASED STUDY
Lydia Trudel, Joseph Therriault, Arthur C. Macedo, Meredith N. Braskie, Karin L. Meeker, Arthur W. Toga, Serge Gauthier, Paolo Vitali, Sid E. O’Bryant, Pedro Rosa-Neto
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Dementia frequently goes undetected in community settings, particularly among socially disadvantaged populations. Here, we estimated the prevalence of underdiagnosed dementia across diverse sociodemographic determinants of health in the Health and Aging Brain Study–Health Disparities (HABS-HD), a community-based cohort of adults recruited through community outreach in Fort Worth, Texas. We estimated age-specific probabilities of underdiagnosis using Poisson regression models with a log link, including age and sex as covariates. Robust (sandwich) variance estimators were used to obtain standard errors and 95% confidence intervals (CI). Group differences or trends for continuous measures were assessed using robust variance estimates. The prevalence of underdiagnosed dementia was higher among individuals without physician access (98.1% vs. 78.1%, p<.0001), non-English speakers (97.9% vs. 76.8%, p<.0001), and the uninsured (91.5% vs. 79.5%, p=.03). Black and Hispanic participants also showed higher prevalence (85.8% and 90.9%) compared to non-Hispanic White participants (64.9%; p=.02 and p=.002, respectively). Each additional year of education was associated with a 2.5% lower risk of underdiagnosis (p<.0001). No differences were observed by sex, marital status, income or social support. Our results highlight that several sociodemographic factors contribute to the likelihood of living with undiagnosed dementia.
CITATION:
Lydia Trudel ; Joseph Therriault ; Arthur C. Macedo ; Meredith N. Braskie ; Karin L. Meeker ; Arthur W. Toga ; Serge Gauthier ; Paolo Vitali ; Sid E. O’Bryant ; Pedro Rosa-Neto (2026): Estimated prevalence of underdiagnosed dementia in a multiethnic community-based study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100510
LETTER TO THE EDITOR : THE FUTURE OF HRT/MHT AND ALZHEIMER’S DISEASE RISK, ONSET AND PROGRESSION
Edwin D. Lephart, Dawson W. Hedges, Frederick Naftolin, Zoe D. Draelos
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CITATION:
Edwin D. Lephart ; Dawson W. Hedges ; Frederick Naftolin ; Zoe D. Draelos (2026): Letter to the Editor: The future of HRT/MHT and Alzheimer’s disease risk, onset and progression. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100508
LECANEMAB FOR TREATMENT OF INDIVIDUALS WITH EARLY ALZHEIMER’S DISEASE (AD) WHO ARE APOLIPOPROTEIN E Ε4 (APOE Ε4) NON-CARRIERS OR HETEROZYGOTES
Richard Perry, Christopher Kipps, Maria Eugenia Soto Martín, Marco Bozzali, Giancarlo Logroscino, Sarah Trafford, Shobha Dhadda, Michio Kanekiyo, Amanda Goodwin, Mark Hodgkinson, Steven Hersch, Michael Irizarry, Lynn Kramer, Lutz Froelich
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BACKGROUND: Lecanemab, an antibody directed at Aβ-protofibrils and plaque, showed meaningful delay in disease progression and biological effects consistent with disease modification in the phase 3 Clarity AD trial.
OBJECTIVE: The objective of this paper is to present efficacy and safety results in ApoE ε4 non-carriers or heterozygotes population of Clarity AD.
DESIGN: Clarity AD is an 18-month, randomized study (core) in participants with early AD, with an open-label extension phase (OLE) phase.
SETTING: Academic and clinical centers.
PARTICIPANTS: All eligible ApoE ε4 participants were randomized 1:1 across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly); the results presented herein are for the ApoE4 heterozygote or non-carrier participants.
MEASUREMENTS: Endpoints included change from baseline at 18 months in the global cognitive and functional scale, CDR-SB, amyloid positron emission tomography (PET), Alzheimer’s Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14), Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL), and health-related quality-of-life (HRQoL) assessments. Amyloid imaging related abnormalities (ARIA) occurrence was monitored throughout the study by central reading of magnetic resonance imaging. Following 18 months treatment in the Core, eligible participants transitioned to the OLE where they received open-label lecanemab. Clinical outcomes (CDR-SB, ADAS-Cog14, and ADCS-MCI-ADL) were evaluated by examining ‘delayed start’ (core:placebo followed by OLE:lecanemab) and ‘early start’ (core:lecanemab followed by OLE:lecanemab) cohorts as well as natural history cohorts. Time to progression to next stage of AD was also evaluated through 36 months.
RESULTS: 1795 participants with early AD were enrolled in Clarity AD, of which 1521 were ApoE ε4 heterozygotes or non-carriers (85 %). Lecanemab significantly reduced clinical decline on CDR-SB at 18 months compared to placebo in the ApoEε4 heterozygotes or non-carriers subgroup. Amyloid PET, ADAS-Cog14, ADCS-MCI-ADL, and HRQoL results were consistent with the CDR-SB findings. In the analysis subgroup, the most common adverse reactions for lecanemab were infusion-related reactions (26 %), ARIA-H (13 %), fall (11 %), headache (11 %), and ARIA-E (9 %). In the OLE, lecanemab-treated participants continued to accrue benefit in CDR-SB through 36 months, with continued separation through 36 months relative to the ADNI natural history cohort. Delayed start results follow a parallel trajectory relative to early start results, but do not catch up, confirming a disease modifying effect and reflecting importance of early treatment initiation. Results were similar for ADAS-Cog14 and ADCS-MCI-ADL. Lecanemab reduced the risk of progression to next stage of AD by 28 % on lecanemab as compared to the ADNI natural history cohort.
CONCLUSION: In the ApoE ε4 heterozygotes or non-carrier subgroup of Clarity AD, lecanemab slowed decline in disease progression and reduced markers of amyloid, with expanding benefit over time.
CITATION:
Richard Perry ; Christopher Kipps ; Maria Eugenia Soto Martín ; Marco Bozzali ; Giancarlo Logroscino ; Sarah Trafford ; Shobha Dhadda ; Michio Kanekiyo ; Amanda Goodwin ; Mark Hodgkinson ; Steven Hersch ; Michael Irizarry ; Lynn Kramer ; Lutz Froelich (2026): Lecanemab for treatment of individuals with early Alzheimer’s Disease (AD) who are apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100507
EVALUATION OF PLASMA P-TAU217 BIOMARKERS IN DETECTING AMYLOID PATHOLOGY AND PREDICTING COGNITIVE OUTCOMES: OBSERVATIONS FROM JAPANESE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE COHORT
Kensaku Kasuga, Masataka Kikuchi, Emiko Kikkawa-Saito, Tamao Tsukie, Takanobu Ishiguro, Akinori Miyashita, Takeshi Iwatsubo, the Japanese Alzheimer’s Disease Neuroimaging Initiative, Takeshi Ikeuchi
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BACKGROUND AND OBJECTIVES: Plasma phosphorylated tau 217 (p-tau217) has shown strong potential as a blood-based biomarker for detecting amyloid pathology in Alzheimer’s disease. This study evaluated the diagnostic and prognostic utility of plasma biomarkers, including p-tau217, in participants from the Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI) cohort.
METHODS: We analyzed paired plasma and CSF samples from 172 J-ADNI participants. CSF and plasma biomarkers were quantified using the LUMIPULSE platform, and the same plasma samples were analyzed using the Simoa platform. The diagnostic accuracy for detecting amyloid pathology and the prognostic value of plasma p-tau217 biomarkers were assessed. Associations between plasma p-tau217 and polygenic risk scores (PRS), as well as potential confounding factors, were examined.
RESULTS: Plasma p-tau217 levels measured using Lumipulse and Simoa assays were highly correlated (p < 0.001). All plasma p-tau217 assays showed high diagnostic accuracy for CSF Aβ42/Aβ40-defined amyloid pathology (AUC = 0.98). A single cutoff point based on the Youden index for p-tau217 and p-tau217/Aβ42 achieved >90% specificity and >90% sensitivity. The predefined FDA-approved two-cutoff model for p-tau217/Aβ42 was applicable to this cohort. PRS was significantly associated with plasma p-tau217 independently of APOE genotypes. Subjects with higher plasma p-tau217 levels showed a significantly increased risk of conversion to dementia and larger longitudinal cognitive declines. Plasma p-tau217 levels were significantly influenced by the body mass index, estimated glomerular filtration rate, and high-density lipoprotein cholesterol.
CONCLUSIONS: Plasma p-tau217 and p-tau217/Aβ42 are robust biomarkers for AD diagnosis and prognosis in the Japanese population.
CITATION:
Kensaku Kasuga ; Masataka Kikuchi ; Emiko Kikkawa-Saito ; Tamao Tsukie ; Takanobu Ishiguro ; Akinori Miyashita ; Takeshi Iwatsubo ; the Japanese Alzheimer’s Disease Neuroimaging Initiative ; Takeshi Ikeuchi (2026): Evaluation of plasma p-tau217 biomarkers in detecting amyloid pathology and predicting cognitive outcomes: Observations from Japanese Alzheimer’s disease neuroimaging initiative cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100502
DIGITAL MEMORY ASSESSMENTS AND PLASMA PTAU217 ENABLE EFFICIENT PRECLINICAL ALZHEIMER’S TRIALS
Casey R. Vanderlip, Daniel L. Gillen, Joshua D. Grill, Craig E.L. Stark
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BACKGROUND: Preclinical Alzheimer’s disease (AD) trials enroll cognitively unimpaired, amyloid-positive older adults; however, most remain clinically stable over typical trial durations. Limited near-term decline reduces statistical power and drives large sample sizes and high costs. Scalable enrichment strategies capable of identifying individuals most likely to decline are critically needed.
OBJECTIVES: To determine whether a brief digital memory assessment (DMA) and plasma phosphorylated tau 217 (pTau217), individually or combined, identify preclinical AD participants at elevated risk for cognitive and biological progression, and whether such enrichment reduces clinical trial sample-size requirements.
DESIGN: Analysis of data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) Study, a multicenter randomized clinical trial with 240 weeks of follow-up.
SETTING: Secondary-prevention trial conducted across sites in the United States, Canada, Australia, and Japan.
PARTICIPANTS: A total of 1,169 cognitively unimpaired adults aged 65–85 years who were amyloid-positive and completed both a baseline DMA and plasma pTau217 measurement.
MEASUREMENTS: Primary outcome was change in the Preclinical Alzheimer Cognitive Composite (PACC) over 240 weeks. Secondary outcomes included Clinical Dementia Rating–Sum of Boxes, Mini-Mental State Examination, Cognitive Function Instrument, and annualized change in amyloid PET, plasma pTau217, and tau PET.
RESULTS: Participants with both elevated pTau217 and low DMA exhibited the greatest cognitive decline and reached the 240-week PACC decline of the overall cohort 83 weeks earlier. Participants with neither marker showed minimal decline. Dual enrichment reduced sample-size estimates for a clinical trial from 3,252 to 818 participants per arm (75 % reduction). These individuals also demonstrated faster increases in plasma pTau217 and neocortical tau PET.
CONCLUSIONS: A brief DMA combined with plasma pTau217 identifies a subset of cognitively unimpaired, amyloid-positive older adults at highest risk for cognitive and biomarker progression. This dual-marker enrichment strategy enables smaller, shorter, and more cost-efficient preclinical AD trials and supports more targeted evaluation of preventive therapies.
CITATION:
Casey R. Vanderlip ; Daniel L. Gillen ; Joshua D. Grill ; Craig E.L. Stark (2026): Digital memory assessments and plasma pTau217 enable efficient preclinical Alzheimer’s trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100503
SPATIAL AMYLOID–INFORMED MULTIMODAL BRAIN AGE AS AN EARLY MARKER OF ALZHEIMER’S-RELATED VULNERABILITY AND RISK STRATIFICATION
Liang Cui, Qing-Min Wang, Zhen Zhang, Min Wang, You-Yi Tu, Jie-Hui Jiang, Yi-Hui Guan, Yue-Hua Li, Fang Xie, Qi-Hao Guo
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BACKGROUND: Brain age gap (BAG)—the difference between predicted and chronological age—captures neurobiological aging, but MRI-only models insufficiently reflect Alzheimer’s disease (AD) pathology. Whether incorporating regional amyloid-β (Aβ) positron emission tomography (PET) improves sensitivity to early AD processes remains unknown.
OBJECTIVES: To develop an amyloid-informed multimodal BAG model and examine its associations with cognition, plasma biomarkers, and functional connectivity across the AD continuum.
DESIGN: Cross-sectional analysis using integrated machine-learning models.
SETTING: Chinese Preclinical Alzheimer’s Disease Study (CPAS), a cohort recruited from community settings and memory clinics.
PARTICIPANTS: Nine hundred ninety community-dwelling adults spanning normal cognition, subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia.
MEASUREMENTS: Regional Aβ-PET and structural MRI informed BAG estimation. Cognitive tests, plasma biomarkers (p-tau217, p-tau181, neurofilament light [NfL], glial fibrillary acidic protein [GFAP], Aβ42/40), and hippocampus–default mode network (DMN) connectivity from resting-state fMRI were assessed.
RESULTS: Higher BAG was associated with greater odds of SCD, MCI, or dementia across the cohort, with stronger effects in Aβ-positive individuals. BAG explained more cognitive variance than global Aβ burden and was linked to multidomain cognitive deficits. Elevated BAG corresponded to higher p-tau217, p-tau181, NfL, and GFAP and lower Aβ42/40, indicating early biomarker alterations. BAG was also associated with reduced hippocampus–DMN connectivity.
CONCLUSIONS: An amyloid-informed multimodal BAG model captures convergent AD-related pathology, biomarker alterations, and cognitive vulnerability beyond amyloid burden alone, supporting its value for individualized risk s2tratification and prevention-focused assessment.
CITATION:
Liang Cui ; Qing-Min Wang ; Zhen Zhang ; Min Wang ; You-Yi Tu ; Jie-Hui Jiang ; Yi-Hui Guan ; Yue-Hua Li ; Fang Xie ; Qi-Hao Guo (2025): Spatial amyloid–informed multimodal brain age as an early marker of Alzheimer’s-related vulnerability and risk stratification. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100501
CUMULATIVE BLOOD PRESSURE AND RISK OF DEMENTIA AND COGNITIVE DECLINE: A SYSTEMATIC REVIEW AND META-ANALYSIS
Ruirui Wang, Yijie Gao, Nicole Ee, Fope Akinyede, Xiaoyue Xu, Linan Chen, Shangzhi Xiong, Xiaoying Chen, Craig S. Anderson, Katie Harris, Ruth Peters
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BACKGROUND AND OBJECTIVE: Cumulative blood pressure (cBP), reflecting long-term BP exposure, is increasingly used to examine risk associations with dementia and cognitive function, but findings to date are inconsistent. This systematic review aimed to synthesize existing evidence to clarify risk associations in adults.
METHODS: We searched for articles in Medline, Embase (Ovid), Web of Science, Cochrane Library, and China National Knowledge Infrastructure from inception to January 2025 in any language. Longitudinal, observational studies involving participants aged over 18 years at the time of initial BP assessment were eligible for inclusion. cBP was defined as the area under the curve of BP values over time or an equivalent method, expressed in units of mmHg × time. Study outcomes were dementia, cognitive function assessments, and neuroimaging markers. This review is registered in PROSPERO (CRD42025640637).
RESULTS: From 6334 records identified, 10 independent prospective cohort studies from 9 publications were included in the review, of which four cohort studies were eligible for meta-analysis. Meta-analysis showed that higher cumulative systolic BP (cSBP) was associated with an increased risk of incident dementia (odds ratio [OR] 1.21, 95% CI 1.00–1.45; I² = 92.4%, P for heterogeneity<0.001), while cumulative diastolic BP (cDBP) was not associated with dementia risk (OR 0.97, 95% CI 0.72–1.32; I²=97.3%, P for heterogeneity<0.001). Among eight studies on cognitive function, five reported that higher cSBP was associated with poorer cognitive performance, while three reported non-significant results. In contrast, findings for higher cDBP were mixed, with two studies reporting adverse associations, two reporting protective associations, and three reporting null associations. Two studies linked higher cSBP and cDBP to greater white matter hyperintensity burden. Sensitivity and subgroup analyses suggested that the positive association between cSBP and dementia-related outcomes were more pronounced among middle-aged adults, whereas inverse or null associations for higher cDBP was observed in some cohorts among individuals aged ≥60 years.
CONCLUSION: Higher cSBP is associated with increased risk of incident dementia and cognitive decline, whereas associations for cDBP are mixed. Given the limited evidence, future studies should incorporate age-stratified analyses and consider including cumulative pulse pressure and mean arterial pressure to further clarify the relationship between cBP and cognition.
CITATION:
Ruirui Wang ; Yijie Gao ; Nicole Ee ; Fope Akinyede ; Xiaoyue Xu ; Linan Chen ; Shangzhi Xiong ; Xiaoying Chen ; Craig S. Anderson ; Katie Harris ; Ruth Peters (2025): Cumulative blood pressure and risk of dementia and cognitive decline: a systematic review and meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100500
LETTER TO THE EDITOR: REFLECTIONS ON THE ROLE OF AI IN ALZHEIMER’S DISEASE RESEARCH: ADDRESSING INCLUSIVITY, CAUSALITY, AND ETHICAL CONSIDERATIONS
Mingyue Chen, Yan Han
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CITATION:
Mingyue Chen ; Yan Han (2026): Letter to the Editor: Reflections on the role of AI in Alzheimer’s disease research: Addressing inclusivity, causality, and ethical considerations. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100488
PRECLINICAL AMYLOID PATHOLOGY IS ASSOCIATED WITH ANXIETY BUT NOT DEPRESSION IN COGNITIVELY NORMAL OLDER ADULTS: EVIDENCE FOR DIFFERENTIAL NEUROPSYCHIATRIC PATHWAYS
Jonathan Vogelgsang, Clara Beck, Regan Patrick, Ipsit Vahia, Sara Weisenbach
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INTRODUCTION: Neuropsychiatric symptoms may represent early Alzheimer's disease (AD) manifestations, but their relationship with amyloid pathology in cognitively unimpaired individuals remains unclear.
METHODS: We analyzed 4,492 cognitively unimpaired adults (aged 65-85) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Study. Participants completed amyloid-PET imaging and assessments of anxiety, depression, memory complaints, and AD concerns.
RESULTS: 1,231 participants (27.4%) were amyloid-positive. While anxiety and depression scores remained within normal ranges, amyloid-positive participants reported higher memory complaints (p = 0.008) and AD concerns (p < 0.001) before status disclosure. Regression analyses showed amyloid burden associated with anxiety (β = 0.04, standardized, p = 0.003) but not depression (p = 0.68). Mediation analyses revealed anxiety was directly associated with amyloid, while depression was mediated through subjective cognitive concerns.
DISCUSSION: Preclinical amyloid pathology directly associates with subclinical anxiety but only indirectly with depression through subjective stress, suggesting distinct neuropsychiatric pathways in early AD that could inform detection strategies.
CITATION:
Jonathan Vogelgsang ; Clara Beck ; Regan Patrick ; Ipsit Vahia ; Sara Weisenbach (2026): Preclinical amyloid pathology is associated with anxiety but not depression in cognitively normal older adults: Evidence for differential neuropsychiatric pathways. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100497
TRAJECTORIES OF SOCIAL PARTICIPATION AND RISK OF COGNITIVE IMPAIRMENT IN CHINESE OLDER ADULTS: A SIX-YEAR LONGITUDINAL STUDY
Kangle Wang, Ruihan Wan, Jiale Peng, Huanghao Zhou, Kaifeng Xu, Hao Liu, Lidian Chen, Zhizhen Liu
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BACKGROUND: The growing burden of cognitive decline represents a significant public health concern in aging populations, particularly in China. Social participation is a modifiable factor that may protect against cognitive decline, yet its long-term dynamic association with cognitive impairment remains insufficiently characterized.
OBJECTIVES: This study aimed to delineate long-term trajectories of social participation and determine their association with cognitive impairment in Chinese older adults.
DESING: Longitudinal cohort study.
SETTING: The study utilized data collected in 2013, 2015, and 2018 from the China Health and Retirement Longitudinal Study.
PARTICIPANTS: We included 3074 Chinese adults aged ≥60 years who were free of cognitive impairment in 2013, had complete social participation data in 2013/2015/2018, and completed cognitive assessments in 2018
INTERVENTION(S): Not applicable.
MEASUREMENTS: Social participation was derived from CHARLS self-reported activity items and frequency and summed into a composite score (range 0–33). Cognitive performance was assessed using episodic memory (immediate and delayed 10-word recall) and mental status (orientation, serial subtraction, and figure drawing), yielding a global score (range 0–31); cognitive impairment was defined as a score <11. Group-based trajectory modeling identified five social participation trajectories. Multivariable logistic regression estimated odds ratios (ORs) for cognitive impairment adjusting for sociodemographic, health, and behavioral covariates.
RESULTS: Five distinct social participation trajectories were identified. In the fully adjusted model, relative to the “stable low” group, those in the “low baseline–increasing” (OR = 0.66, 95% CI: 0.47–0.92), “stable intermediate” (OR = 0.75, 95% CI: 0.58–0.97), and “stable high” (OR = 0.41, 95% CI: 0.22–0.76) groups had markedly reduced chances of cognitive impairment, while no significant link was found for the “moderate decline” group (OR = 0.90, 95% CI: 0.71–1.17).
CONCLUSIONS: Maintaining or increasing one’s social activities was linked to a notably lower likelihood of cognitive decline. These results highlight the importance of social involvement patterns as a modifiable factor for fostering cognitive strength. Interventions to maintain or enhance participation are therefore a viable strategy for the primary prevention of cognitive decline in older adults.
CITATION:
Kangle Wang ; Ruihan Wan ; Jiale Peng ; Huanghao Zhou ; Kaifeng Xu ; Hao Liu ; Lidian Chen ; Zhizhen Liu (2026): Trajectories of social participation and risk of cognitive impairment in Chinese older adults: A six-year longitudinal study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100499
EXPERIMENTAL AND TRANSLATIONAL MODELS OF ALZHEIMER’S DISEASE: FROM NEURODEGENERATION TO NOVEL THERAPEUTIC INSIGHTS
Nadeemullah Khan, Somnath De, Suhasini Boddu, Navya Pravala
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Neurodegeneration on demand represents a groundbreaking approach to modeling Alzheimer’s disease (AD) in animals, enabling precise study of its molecular and behavioral hallmarks. Novel techniques, including optogenetic activation of amyloidogenic pathways, viral vector-mediated delivery of mutated human genes (e.g., APP, MAPT), and synthetic tau fibril analogs, induce AD-like pathology, including amyloid-beta plaques, tau hyperphosphorylation, neuroinflammation, and synaptic loss in diverse species, ranging from transgenic rodents to cephalopods and cannies. Emerging platforms, such as bioengineered neural organoids grafted into immunocompromised hosts, allowed for the controlled onset of AD-like features, providing unique insights into disease progression. Advanced tools like real-time neuroimaging and single-cell multi-omics help elucidate the temporal and cellular dynamics of neurodegeneration. These models provided unparalleled opportunities to dissect AD’s complex mechanisms, including protein misfolding, glial dysregulation, and cognitive decline. However, challenges remained, including interspecies molecular disparities, incomplete replication of human AD complexity, and ethical concerns surrounding cognitive impairment in sentient models. This review explores these innovative strategies, their contributions to understanding AD’s pathogenesis, and their potential to accelerate the development of transformative therapies, while also addressing limitations and future directions for refining these pioneering models.
CITATION:
Nadeemullah Khan ; Somnath De ; Suhasini Boddu ; Navya Pravala (2026): Experimental and translational models of Alzheimer’s disease: From neurodegeneration to novel therapeutic insights. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100498
ASSOCIATION OF CARDIAC BIOMARKERS WITH LONGITUDINAL COGNITIVE CHANGES IN THE GENERAL POPULATION
Fang-Fei Wei, Dubo Chen, Chaoxin Xu, Zhongping Yu, Zihao Chen, Chang Chen, Xin He, JingJing Zhao, Wenqing Li, Cuiping Zhao, Jiangui He, Yugang Dong, Jan A. Staessen, Chen Liu
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BACKGROUND: Little is known about the association of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) with changes in cognitive performance over time.
OBJECTIVES: To investigate the association of cardiac biomarkers with cognitive changes over time.
PARTICIPANTS: The study population consisted of 2540 stroke-free participants (56.1 % women; 21.2 % Black; mean age, 74.5 years) enrolled in the Atherosclerosis Risk in Communities study.
MEASUREMENTS: Associations of the changes in the Mini Mental State Examination (MMSE) scores with the log-transformed cardiac biomarkers were modelled using multivariable linear and restricted cubic spline regression.
RESULTS: Over 6.6 years (median), the MMSE score decreased by 0.57 (95 % CI, 0.46–0.67) and the frequency of an MMSE score <24 increased from 5.339 % to 9.69 % (P < 0.001). In multivariable-adjusted models, the cardiac biomarkers measured at baseline were linearly related to absolute MMSE changes with association sizes amounting to 0.47 (0.27–0.66) and 0.58 (0.19–0.97) for NT-proBNP and hs-cTnT, respectively. Classification-by-cardiac biomarker interactions were significant for race, age group and diabetes in relation to NT-proBNP (P ≤ 0.031) and for race, age group and hypertension in relation to hs-cTnT (P ≤ 0.041). For both biomarkers, associations were stronger in Blacks than Whites and in older than younger individuals; for NT-proBNP in diabetic than non-diabetic participants; and for hs-cTnT in normotensive than hypertensive individuals.
CONCLUSION: NT-proBNP and hs-cTnT were associated with MMSE changes. Although association studies cannot prove causality, the clinical implication might be that targeting the heart within the framework of a multifactorial approach might be strategy in reducing cognitive decline.
CITATION:
Fang-Fei Wei ; Dubo Chen ; Chaoxin Xu ; Zhongping Yu ; Zihao Chen ; Chang Chen ; Xin He ; JingJing Zhao ; Wenqing Li ; Cuiping Zhao ; Jiangui He ; Yugang Dong ; Jan A. Staessen ; Chen Liu (2026): Association of cardiac biomarkers with longitudinal cognitive changes in the general population. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100494
LETTER TO THE EDITOR : RE-THINKING FUNDING SUCCESS IN ALZHEIMER’S DISEASE RESEARCH: WHY GOOD SCIENCE IS NOT ENOUGH
Peter Fusdahl, Miguel G. Borda, Dag Aarsland
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CITATION:
Peter Fusdahl ; Miguel G. Borda ; Dag Aarsland (2026): Long-term fasting insulin variability and cognitive function: Insights from tRe-thinking funding success in Alzheimer’s disease research: Why good science is not enoughhe CARDIA study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100496
LONG-TERM FASTING INSULIN VARIABILITY AND COGNITIVE FUNCTION: INSIGHTS FROM THE CARDIA STUDY
Bo-Shui Huang, Zuo-Yu Huang, Yu-Hong Zeng, Kun-Hao Bai, Jing-Bin Guo, Jun Weng, Ze-Hua Li, Qing-Yun Hao
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BACKGROUND AND AIM: Fasting insulin variability has emerged as a potential marker of metabolic dysregulation, but its long-term implications for cognitive function remain unclear. This study aimed to clarify the role of long-term fasting insulin variability in predicting individual cognitive function risk.
METHODS: We analyzed data from CARDIA study participants who underwent cognitive testing and had at least three insulin measurements. Fasting insulin was measured at 7 timepoints over 30 years. Intra-individual insulin variability was assessed using standard deviation (SD), coefficient of variation (CV), and average real variability (ARV). Cognitive function was evaluated using the Digit Symbol Substitution Test (DSST), Stroop Test, and Rey Auditory Verbal Learning Test (RAVLT), with results standardized to z-scores and combined into a global cognitive z-score. Multivariable linear models were used to assess associations with cognitive performance.
RESULTS: In the 25-year analysis (n = 2712), higher long-term insulin variability was significantly associated with poorer global cognitive performance at year 25 after adjustment for demographic, lifestyle, and cardiometabolic covariates (CV-insulin: β=–0.719; 95% CI: –1.161 to –0.276; P < 0.01; SD-insulin: β=–0.019; 95% CI: –0.036 to –0.002; P < 0.05). These associations remained significant after additional adjustment for either concurrent insulin at year 25 or mean insulin levels over 25 years. Domain-specific analyses showed that higher insulin variability was associated with lower DSST z-scores (worse attention) and higher Stroop interference z-scores (worse executive function). Extended analyses over 30 years (n = 2069) yielded consistent results: higher CV-insulin was inversely associated with global cognitive z-scores (β=–0.837; 95% CI: –1.347 to –0.327), as well as with DSST (β=–0.347; 95% CI: –0.581 to –0.112) and RAVLT z-scores (β=–0.276; 95% CI: –0.522 to –0.031). These associations persisted after full adjustment for year 30 covariates and time-varying confounders across the follow-up, supporting the temporal robustness and clinical relevance of insulin variability as an independent predictor of cognitive function.
CONCLUSIONS: Greater long-term insulin variability is independently associated with poorer midlife cognitive performance. These findings highlight insulin variability as a potential marker of cognitive health risk.
CITATION:
Bo-Shui Huang ; Zuo-Yu Huang ; Yu-Hong Zeng ; Kun-Hao Bai ; Jing-Bin Guo ; Jun Weng ; Ze-Hua Li ; Qing-Yun Hao (2026): Long-term fasting insulin variability and cognitive function: Insights from the CARDIA study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100487
JPAD Volume 13, N°03 - 2026
EDITORIAL: LOW NUMBER OF PATIENTS QUALIFYING FOR AMYLOID TARGETING IMMUNOTHERAPY
Frank Jessen
J Prev Alz Dis 2026;3(13)
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CITATION:
Frank Jessen (2026): Low number of patients qualifying for amyloid targeting immunotherapy. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100516
PREPARING FOR THE IMPLEMENTATION OF ANTI-AMYLOID THERAPIES IN EUROPE: ASSESSING REAL-WORLD ELIGIBILITY FOR LECANEMAB AND DONANEMAB IN A SWEDISH MEMORY CLINIC
Anna Rosenberg, Alina Solomon, Alexandre Bonnard, Makrina Daniilidou, Göran Hagman, Anette Hall, Anna Matton, Ulf Öhlund-Wistbacka, Eric Westman, Miia Kivipelto
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryLecanemab and donanemab are the first anti-Aβ treatments to receive approval in Europe. Eligibility criteria are strict, eg., APOE ε4/4 carriers are excluded. Successful implementation in public healthcare hinges on accurate estimates of eligibility rates in settings which will be the first to roll out the treatments (specialized memory clinics with early disease stages). We applied the appropriate use recommendations (AUR) to assess treatment eligibility in a Swedish tertiary memory clinic where Aβ and APOE assessments are routinely performed. Of the full cohort (N = 410), 26 and 25 patients met the AUR criteria for lecanemab and donanemab, respectively (6 %; partial overlap between the groups). After excluding APOE ε4/4 carriers in line with the European guidelines, only 14 and 13 patients remained eligible (3 %). In clinics with younger populations, a significant percentage of potentially eligible patients are likely to have the APOE ε4/4 genotype. These findings are important to inform the implementation of anti-Aβ treatments.
CITATION:
Anna Rosenberg ; Alina Solomon ; Alexandre Bonnard ; Makrina Daniilidou ; Göran Hagman ; Anette Hall ; Anna Matton ; Ulf Öhlund-Wistbacka ; Eric Westman ; Miia Kivipelto (2025): Preparing for the implementation of anti-amyloid therapies in Europe: Assessing real-world eligibility for lecanemab and donanemab in a Swedish memory clinic. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100476
BRAIN HEALTH NAVIGATION IN A LARGE INTEGRATED HEALTHCARE SYSTEM
G.E. Cooper, S. Patton, D. Lockridge, S.W. Freeman, D. Drexler, K. Wasz
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryAlzheimer’s Disease is a complex, chronic illness of increasing prevalence in the US and worldwide. The complexity of this illness, and its impact on caregivers make it an ideal candidate for navigation services. The development of billable navigation codes now make it possible to create a financially sustainable navigation program. We describe our initial experience with a brain health navigator program, partnering between primary and specialty memory care, in a large integrated healthcare system. While a number of challenges exist, and careful planning was required, we have successfully implemented a navigation program, enrolling greater than 100 patients in the initial 6 months. Patient and caregiver feedback has been highly positive. We have experienced no significant barriers to reimbursement and when accounting for incremental downstream revenue generation (e.g. MRI, labs), we are forecasting long-term financial sustainability and the opportunity for continued scaling over time.
CITATION:
G.E. Cooper ; S. Patton ; D. Lockridge ; S.W. Freeman ; D. Drexler ; K. Wasz (2025): Brain health navigation in a large integrated healthcare system. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100471
NO LONGITUDINAL ASSOCIATION BETWEEN HEARING LOSS AND ALZHEIMER’S DISEASE PATHOLOGY
Jordi H.C. Boons, Phuong Thuy Nguyen Ho, Anna van Houwelingen, M. Arfan Ikram, Gertjan Dingemanse, Bernd Kremer, Meike W. Vernooij, Andre Goedegebure, Julia Neitzel
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryINTRODUCTION: Hearing loss (HL) is a potential risk factor for Alzheimer’s disease (AD), with animal studies suggesting a bidirectional relationship. This study examines whether HL links to changes in AD pathology and, whether AD biomarkers relate to subsequent HL progression.
MEHODS: Baseline Aβ42/Aβ40 and p-tau217 were measured using single-molecule arrays in 474 participants of the Rotterdam Study (mean age=62.37) between 2010-2016. HL was defined as the better-ear’s pure-tone threshold average. After seven years, participants underwent amyloid PET; HL and p-tau217 were reassessed two years after PET.
RESULTS: Baseline HL was not associated with amyloid PET positivity, Aβ42/Aβ40, or longitudinally with p-tau217. Likewise, HL progression did not predict PET outcomes. APOE4 carriership did not modify associations with Aβ PET. Similarly, baseline plasma biomarkers were also unrelated to longitudinal HL changes.
CONCLUSION: No bidirectional association was observed between HL and AD pathology, suggesting that HL may contribute to dementia through other pathways.
CITATION:
Jordi H.C. Boons ; Phuong Thuy Nguyen Ho ; Anna van Houwelingen ; Arfan Ikram ; Gertjan Dingemanse ; Bernd Kremer ; Meike W. Vernooij ; Andre Goedegebure ; Julia Neitzel (2026): No longitudinal association between hearing loss and Alzheimer’s disease pathology. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100481
ASSOCIATIONS OF SELF- AND INFORMANT-REPORTED FUNCTIONAL IMPAIRMENT WITH COGNITIVE PERFORMANCE AND INCIDENT DEMENTIA
Yaqing Gao, Paola Zaninotto, Andrew Steptoe
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryINTRODUCTION: Functional impairment is central to dementia diagnosis, typically assessed through basic and instrumental activities of daily living (ADLs/IADLs) reported by participants or informants. However, it remains unclear which items and reporting sources best capture cognition-related functional impairment.
METHODS: We analysed data from 1,050 adults aged ≥65 years in the English Longitudinal Study of Ageing Harmonised Cognitive Assessment Protocol. Self- and informant-reported ADL and IADL impairments were examined at overall and item levels. Associations with general and domain-specific cognition were estimated using linear regression, and with incident dementia over 6.7 years using Cox models, both adjusted for socioeconomic, lifestyle, and health factors.
RESULTS: ADL and IADL impairment proportions were similar across self- and informant-reports, with modest concordance. Informant-reported, but not self-reported, impairments were consistently associated with poorer cognition across domains, particularly executive function (informant-reported ADL: β = –0.71 SD, 95% CI –0.89 to –0.53) and memory (informant-reported IADL: β = –0.46 SD, 95% CI –0.60 to –0.32), and higher dementia risk (ADL: HR = 3.13, 95% CI 1.23 to 7.96; IADL: HR = 5.00, 95% CI 2.40 to 10.43). The strongest associations were observed for managing money and tasks involving episodic or visuospatial memory, especially among individuals with intermediate education and when informants had higher education or daily contact.
DISCUSSION: Informant-reported IADLs, particularly those involving financial management and memory, may be strong indicators of cognitive impairment and dementia risk. Emphasising these items and informant characteristics may improve population surveillance of dementia and inform outcome selection in preclinical dementia trials targeting early functional decline. These findings should be interpreted in the context of a population-based sample with attrition.
CITATION:
Yaqing Gao ; Paola Zaninotto ; Andrew Steptoe (2026): Associations of self- and informant-reported functional impairment with cognitive performance and incident dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100482
PHASE 3 RANDOMIZED CLINICAL TRIALS OF SIMUFILAM IN MILD-TO-MODERATE ALZHEIMER’S DISEASE
James W. Kupiec, Anton P. Porsteinsson, Raymond S. Turner, Suzanne Hendrix, Craig Mallinckrodt, Arifulla Khan, Ian Cohen, Jonathan Liss, Roger Clarnette, Kee Hyung Park, Antonio M. Hernandez, Lindsay H. Burns
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: Soluble amyloid β1–42 (Aβ42) signals via the α7 nicotinic acetylcholine receptor to hyperphosphorylate tau in Alzheimer's disease (AD). Simufilam disrupts this pathogenic signaling by binding filamin A and disrupts its linkages with inflammatory receptors to reduce neuroinflammation. We assessed simufilam in two Phase 3 clinical trials in mild-to-moderate AD.
METHODS: Participants were age 50–87 with Stage 4 or 5 CE, a mini-mental state exam (MMSE) ≥16 and ≤27 and a Clinical Dementia Rating Global Score (CDR-GS) of 0.5, 1 or 2. The criterion supporting AD pathology was plasma phosphorylated (p)-tau181 or prior amyloid PET. RETHINK randomized participants to simufilam 100 mg or placebo for 52 weeks. REFOCUS evaluated simufilam 50 and 100 mg versus placebo for 76 weeks. Co-primary endpoints were change from baseline on ADAS-Cog12 and ADCS-ADL. Sub-studies assessed exploratory plasma biomarkers and, in REFOCUS only, CSF and imaging biomarkers.
RESULTS: Both trials failed to meet co-primary, secondary or exploratory biomarker endpoints. REFOCUS was terminated early, with 22% of participants still active in the trial. In the predefined mild subgroup in REFOCUS, simufilam was associated with slower cognitive decline than placebo through Week 64 (p = 0.019). This finding disappeared at Week 76 with 45% missing data and did not replicate in RETHINK. Favorable nominal exploratory post-hoc findings amongst participants with the highest half of screening plasma p-tau181 levels occurred in RETHINK but not REFOCUS. The plasma p-tau181 entry criterion did not reliably exclude amyloid PET negativity in the sub-study.
CONCLUSIONS: Simufilam did not meet co-primary or secondary endpoints in these Phase 3 trials. Simufilam was safe and well tolerated. Trials registered at clinicaltrials.gov: NCT04994483 and NCT05026177.
CITATION:
James W. Kupiec ; Anton P. Porsteinsson ; Raymond S. Turner ; Suzanne Hendrix ; Craig Mallinckrodt ; Arifulla Khan ; Ian Cohen ; Jonathan Liss ; Roger Clarnette ; Kee Hyung Park ; Antonio M. Hernandez ; Lindsay H. Burns (2025): Phase 3 randomized clinical trials of simufilam in mild-to-moderate Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100469
CLINICAL, IMAGING AND BLOOD BIOMARKER OUTCOMES IN A PHASE 3 CLINICAL TRIAL OF TAU AGGREGATION INHIBITOR HYDROMETHYLTHIONINE MESYLATE IN MILD COGNITIVE IMPAIRMENT AND MILD TO MODERATE DEMENTIA DUE TO ALZHEIMER’S DISEASE
Claude M Wischik, Richard Stefanacci, 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, Lewis K Penny, Mohammad Arastoo, Roger Staff, Anca-Larisa Sandu, Helen Shiells, Serena Lo, Nafeesa Nazlee, Emily Evans, Claire Hull, Bjoern O Schelter
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: Hydromethylthionine mesylate (HMTM) targets tau pathology and has tau-independent symptomatic activity.
OBJECTIVES: To evaluate the safety and efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer’s disease (AD).
SETTING: 82 centres in Canada, European Union, United Kingdom and United States of America.
PARTICIPANTS: A total of 598 amyloid β-PET positive participants were included; 44% (263) met clinical criteria for MCI due to Alzheimer’s disease and 56% (335) were diagnosed with mild to moderate dementia due to AD. Intervention: HMTM 16 mg/day and 8 mg/day were compared with methylthioninium chloride (MTC) 4 mg twice weekly, intended as an inactive urinary colourant to preserve blinding with respect to possible urinary discolouration caused by HMTM.
MEASUREMENTS: HMTM and MTC were compared on cognitive and functional endpoints for the first 52 weeks followed by all receiving HMTM 16 mg/day to 104 weeks in a modified delayed-start trial design. Biomarker outcomes included change in plasma levels of neurofilament light chain (NfL), pTau217 and MRI measures of grey matter atrophy.
RESULTS: It was not possible to demonstrate significant differences on the co-primary clinical endpoints (ADAS-cog11 and ADCS-ADL23) at 52 weeks due to symptomatic activity in the control arm. In participants with MCI, statistically significant differences in cognitive decline (ADAS-cog13) emerged at 78 weeks (p = 0·0291) and 104 weeks (p = 0·0308) between early- and delayed-start HMTM 16 mg/day in analyses specified prior to the 24-month database lock. Statistically significant cognitive improvement over baseline score was sustained for 78 weeks in the early start MCI group, with no significant cognitive or functional decline to 104 weeks. There was a significant reduction in progression of neurodegeneration measured by NfL change (p = 0·0291) at 52 weeks in the whole population, consistent with significant reductions in progression of grey matter atrophy at 52 and 104 weeks, and a reduction in progression of tau pathology (pTau217, p = 0·0165) in MCI. Headache (1·5%) and diarrhoea (1·2%) were the most frequent adverse effects.
CONCLUSIONS: Although HMTM 16 mg/day arrested progression of neurodegeneration and reduced grey matter atrophy at 52 weeks, symptomatic activity in the control arm precluded separation of treatment arms at 52 weeks on primary clinical endpoints. In participants with MCI, significant clinical separation was seen only at 78 and 104 weeks. This effect has been confirmed in a further study. HMTM was well tolerated and has the potential to offer an accessible oral treatment option with a benign safety profile which could be delivered with minimal patient/physician burden.
CITATION:
Claude M Wischik ; Richard Stefanacci ; 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 ; Lewis K Penny ; Mohammad Arastoo ; Roger Staff ; Anca-Larisa Sandu ; Helen Shiells ; Serena Lo ; Nafeesa Nazlee ; Emily Evans ; Claire Hull ; Bjoern O Schelter (2026): Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100480
SAFETY PROFILES OF LECANEMAB: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS AND REAL-WORLD EVIDENCE
Lin Qi, Fangxue Zheng, Mengjiao Tu, Reema Abdullah, Yilei Zhao, Xinhui Su, Dan Zhou, Guoping Peng
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: Safety profiles of lecanemab, an anti-amyloid-β antibody for the treatment of early Alzheimer’s disease (AD), remain uncertain and may vary between randomized controlled trials (RCTs) and real-world evidence (RWE) studies.
OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the safety, tolerability, and acceptability of lecanemab based on findings from both RCTs and emerging RWE studies.
METHODS: We systematically searched major databases and clinical trial registries from their inception to June 2025. Random-effects meta-analyses were performed to estimate the pooled incidence of key safety outcomes, including amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation (due to ARIA, adverse events [AEs], or any cause). The risk of ARIA according to the ApoE4 genotype was assessed via relative risk (RR). This study was registered with PROSPERO (No. CRD420251110679).
RESULTS: A total of two RCTs and five RWE studies encompassing 1576 patients were included. The pooled ARIA incidence was 19% (95% CI: 16%-23%), which was significantly modulated by ApoE4 status (RR 1.45 for heterozygotes, 3.54 for homozygotes vs noncarriers) and the pooled symptomatic ARIA incidence was 3% (95% CI: 2%-4%). IRRs occurred in 26% (95% CI: 19%–34%), with heterogeneity reduced in patients receiving specific pre-infusion prophylaxis. The pooled rate of discontinuation due to AEs was 8% (95% CI: 5%-11%), with discontinuation due to ARIA occurring in 5% (95% CI: 3%-7%) of patients in RWE studies.
CONCLUSIONS: Lecanemab-related ARIA demonstrates a clear ApoE4 gene-dose effect, supporting routine ApoE4 genotyping before treatment. Standardizing pre-infusion prophylaxis may reduce variability in IRRs incidence, while prompt recognition and management of ARIA are critical for improving treatment tolerability. These findings provide important evidence to support the safe clinical use of lecanemab.
CITATION:
Lin Qi ; Fangxue Zheng ; Mengjiao Tu ; Reema Abdullah ; Yilei Zhao ; Xinhui Su ; Dan Zhou ; Guoping Peng (2025): Safety profiles of lecanemab: A systematic review and meta-analysis of randomized controlled trials and real-world evidence. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100473
A REGIONAL FRAMEWORK FOR THE DETECTION AND MANAGEMENT OF ARIA WITH ANTI-AMYLOID THERAPIES IN EARLY ALZHEIMER’S DISEASE IN ASIA
So Young Moon, Ta-Fu Chen, Bo-Ching Lee, Won Jin Moon, Nagaendran Kandiah, Sumeet Kumar, Young Ho Park, Kaori Inaba, Amitabh Dash
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryAlzheimer’s disease (AD) is a growing public health concern in Asia, with an increasing prevalence driven by demographic shifts and rising life expectancy. The introduction of anti-amyloid monoclonal antibodies such as lecanemab and donanemab marks a pivotal transition from symptomatic management of AD to disease-modifying approaches, but their clinical use requires careful monitoring for amyloid-related imaging abnormalities (ARIA), a key safety consideration that presents either as vasogenic edema or as microhemorrhages and superficial siderosis. ARIA has been observed in varying frequencies across global and Asian clinical trial populations, underscoring the need for region-specific guidance. With our early clinical experiences in South Korea, Taiwan and Singapore serving as archetypes in Asia, we outline a framework for the detection and management of ARIA in Asian healthcare settings, accounting for disparities in imaging infrastructure, genetic factors, and clinician experience. Pre-treatment risk stratification, standardized imaging protocols, and severity-based treatment modifications are central to the framework, highlighting the critical role of multidisciplinary collaboration involving neurologists, geriatricians, psychiatrists, and radiologists in ensuring accurate detection and management of ARIA. Additionally, the paper highlights the role of pharmacovigilance, real-world evidence generation, physician education, and healthcare system preparedness in optimizing the safety and efficacy of anti-amyloid therapies in Asia. The proposed framework aims to ensure safe and effective use of anti-amyloid therapies while mitigating ARIA-related risks, thereby optimizing therapeutic outcomes for early AD in diverse healthcare settings across Asia.
CITATION:
So Young Moon ; Ta-Fu Chen ; Bo-Ching Lee ; Won Jin Moon ; Nagaendran Kandiah ; Sumeet Kumar ; Young Ho Park ; Kaori Inaba ; Amitabh Dash (2026): A regional framework for the detection and management of ARIA with anti-amyloid therapies in early Alzheimer’s disease in Asia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100477
THE INFLUENCE OF BAPINEUZUMAB AND SEMAGACESTAT ON RAPID PROGRESSORS: A RETROSPECTIVE COHORT STUDY
Kristofer Harris, Madison Shyer, Dulin Wang, Elizabeth He, Matias Cattani, Catherine Zhang, Christine M. Farrell, Xiaoqian Jiang, Yejin Kim, Paul E. Schulz
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: A subset of Alzheimer's disease patients progresses much more rapidly than average. These rapid progressors exhibit accelerated cognitive and functional decline. Potential differences in Alzheimer’s biomarkers for rapid progressors and their responses to disease-modifying treatments remain poorly understood, with previous clinical trials and studies producing limited biomarker data and inconsistent results.
OBJECTIVES: Examine differences in rapid progressor versus non-rapid progressor outcomes in two AD treatment trials (bapineuzumab and semagacestat) and investigate cognitive and biomarker progression in the placebo groups.
DESIGN: Retrospective cohort study.
SETTING: Four randomized, double-blind, phase 3 clinical trials from the Center for Global Clinical Research Data (Semagacestat) and the Yale University Open Data Access Project (Bapineuzumab).
PARTICIPANTS: 4,902 patients (2,355 in bapineuzumab trials, 2,647 in semagacestat trials). Rapid progressors were operationally defined as the 10% of patients with the largest changes in cognitive scores from baseline to trial end.
INTERVENTION: Bapineuzumab (monoclonal antibody) and Semagacestat (γ-secretase inhibitor).
MEASUREMENTS: Cognitive assessments (CDR-SB, MMSE, ADAS-Cog, ADCS-ADL) and biological markers (CSF and plasma levels, MRI, FDG PET Scan, and Amyloid PET Scan) at baseline and endpoint.
RESULTS: Rapid progressors showed distinct baseline characteristics in both the bapineuzumab and semagacestat trials: younger age (61.27 vs 63.14 years, p=0.008; and, 72.64 v. 73.64 years, p=0.046), a higher proportion of APOE4 carriers (87.6% vs 41.4%, p<0.001; and, 85.2% vs 49.3%, p = 0.022), and greater cognitive impairment across all measures (p<0.001). Both progression groups demonstrated improvement in specific biomarkers with treatment, though with different patterns. With bapineuzumab according to Conditional Average Treatment Effect analysis, rapid progressors showed biomarker improvement in amyloid CSF, p-Tau CSF, and amyloid PET scan, while non-rapid progressors demonstrated biomarker improvements in p-Tau CSF, amyloid PET, and MRI. With semagacestat, rapid progressors showed improvements in amyloid CSF and plasma while non-rapid progressors showed improvements in amyloid CSF, FDG PET, and MRI.
CONCLUSIONS: This study provides crucial insights for clinical practice and trial design. The distinct response patterns between progression groups suggest that early identification and balancing of RPs between groups could improve clinical trial efficiency. The findings support the development of personalized treatment approaches for rapid progressors, who have aggressive disease progression. These results may significantly modify clinical trial design and patient care in Alzheimer’s disease.
CITATION:
Kristofer Harris ; Madison Shyer ; Dulin Wang ; Elizabeth He ; Matias Cattani ; Catherine Zhang ; Christine M. Farrell ; Xiaoqian Jiang ; Yejin Kim ; Paul E. Schulz (2026): The influence of bapineuzumab and semagacestat on rapid progressors: A retrospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100483
LECANEMAB OVER A TWO-YEAR DURATION: KEY INSIGHTS FROM A REGIONAL SPECIALTY MEDICAL CENTER
Lisa B.E. Shields, Hust Hannah, Gregory E. Cooper, Theresa Kluthe, Rachel N. Hart, Andrew P. Thaliath, Brandon C. Dennis, Stephanie W. Freeman, Jessica F. Cain, Whoy Y. Shang, Kendall M. Wasz, Adam T. Orr, Christopher B. Shields, Shirish S. Barve, Kenneth G. Pugh
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND AND OBJECTIVES: The anti-amyloid monoclonal antibody lecanemab (Leqembi®) treats patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease (AD). We sought to evaluate the incidence of amyloid-related imaging abnormalities) ARIA and other adverse events associated with lecanemab.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective and observational study features 187 patients who received at least one lecanemab infusion at our multidisciplinary Norton Neuroscience Institute Memory Center over a two-year duration (August 25, 2023-August 24, 2025).
RESULTS: A total of 109 (58.3 %) patients were diagnosed with MCI, and 78 (41.7 %) had mild dementia prior to starting lecanemab. The mean age at the initial infusion was 73 years (Range: 49-90 years). Most (127 [67.9 %]) patients were female, and the majority (181 [96.8 %]) were Caucasian. Of the 175 patients who underwent at least one surveillance brain MRI following lecanemab initiation, 39 (22.3 %) had evidence of ARIA (both ARIA-H and ARIA-E: 13 [33.3 %]; solitary ARIA-H: 17 [43.6 %]; and solitary ARIA-E: 9 [23.1 %]). Of these 39 patients, 20 (51.3 %) were ε4 heterozygous, 12 (30.8 %) were ε4 homozygous, and 7 (17.9 %) were ε4 non-carriers. Patients who were ε4 homozygous more frequently had evidence of any ARIA (p-value = 0.002), ARIA-E (p = 0.041), and ARIA-H (p = 0.004). Of the 25 patients who underwent at least one surveillance brain MRI and were ε4 homozygous, 12 (48.0 %) had ARIA detected. Five (12.8 %) patients with ARIA were symptomatic, requiring lecanemab suspension. Three of these symptomatic patients were ε4 homozygous, and two were ε4 heterozygous. The ARIA was most frequently detected on the surveillance brain MRI performed before the 5th infusion (29 [74.4 %] patients). All 39 cases of ARIA occurred before the 14th lecanemab infusion. Patients with more baseline microbleeds more frequently developed any ARIA (ARIA-H and ARIA-E) (p = 0.041) and solitary ARIA-H (p = 0.022). The presence of baseline microbleeds was associated with a higher frequency of solitary ARIA-H, though was only marginally statistically significant (p = 0.051). Sixty (32.1 %) patients experienced infusion-related adverse effects, with 54 (90.0 %) occurring after the first lecanemab infusion. Mild and transient headaches were most common, affecting 26 (48.1 %) of these patients after the first infusion. After initiating a pre-infusion oral cocktail of acetaminophen 650 mg, loratadine 10 mg, and famotidine 20 mg, the number of patients who experienced an infusion-related adverse event decreased from 45.2 % to 28.3 %. Thirty-two (17.1 %) patients discontinued lecanemab, primarily due to cognitive decline associated with progressive AD (10 [31.2 %]) and ARIA progression (9 [28.1 %]). Of the 73 patients who had MMSE scores performed at baseline and after 1 year post-lecanemab, 13 (17.8 %) had increased scores, 51 (69.9 %) had decreased scores, and the scores remained the same in 9 (12.3 %) patients.
CONCLUSIONS: Our findings suggest that ARIA is a significant concern especially in patients who are ε4 homozygous. Close monitoring of patients who are ε4 carriers is recommended to recognize any complications that may ensue.
CITATION:
Lisa B.E. Shields ; Hust Hannah ; Gregory E. Cooper ; Theresa Kluthe ; Rachel N. Hart ; Andrew P. Thaliath ; Brandon C. Dennis ; Stephanie W. Freeman ; Jessica F. Cain ; Whoy Y. Shang ; Kendall M. Wasz ; Adam T. Orr ; Christopher B. Shields ; Shirish S. Barve ; Kenneth G. Pugh (2026): Lecanemab over a two-year duration: Key insights from a regional specialty medical center. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100489
PLASMA AΒ42/AΒ40 DETERMINED BY MASS SPECTROMETRY IS ASSOCIATED WITH LONGITUDINAL CHANGES IN AMYLOID ACCUMULATION, BRAIN ATROPHY, AND CONVERSION TO MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER’S DISEASE IN INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE: 5-YEAR FOLLOW-UP OF THE FACEHBI COHORT
Noelia Fandos, María Pascual-Lucas, Leticia Sarasa, Jose Terencio, Mª Eugenia Sáez, Juan Pablo Tartari, Ángela Sanabria, Oscar Sotolongo-Grau, Amanda Cano, Lluís Tárraga, Miren Jone Gurruchaga, Agustín Ruíz, Xavier Montalban, Mercè Boada, Montserrat Alegret, Marta Marquié, José Antonio Allué, on behalf of the FACEHBI study group, on behalf of the AMYPAD consortium
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: The accurate identification of individuals at risk of Alzheimer’s disease (AD) through blood-based biomarkers remains challenging.
OBJECTIVES: To evaluate the association between plasma amyloid-beta (Aβ)42/Aβ40 ratio and longitudinal amyloid deposition, clinical progression, brain atrophy and cognitive decline.
DESIGN, SETTING AND PARTICIPANTS: This study extends the Fundació ACE Healthy Brain Initiative (FACEHBI) study (Barcelona, Spain), comprising 200 individuals with subjective cognitive decline (SCD) followed over five years.
MEASUREMENTS: Aβ42/Aβ40 ratio was quantified using ABtest-MS, an antibody-free mass-spectrometry (MS) method. Survival analyses compared conversion risks to amyloid-PET positivity and mild cognitive impairment (MCI), in participants classified as low or high Aβ42/Aβ40, based on a cutoff of ≤ 0.241. Linear mixed-effect models evaluated associations of this biomarker with longitudinal changes in amyloid deposition, brain volume, and cognition.
RESULTS: Low baseline Aβ42/Aβ40 was significantly associated with increased amyloid accumulation (β = 0.257, 95% confidence interval (CI) 0.177–0.336, P < 0.001), and with higher risk of conversion to Aβ-PET positivity (Hazard ratio (HR) = 2.84, 95% CI 1.14–7.04, P = 0.025) and to MCI due to AD (HR = 3.25, 95% CI 1.17–9.01, P = 0.024). It was also linked to decreased hippocampal (β = -1.183, 95% CI -2.154 to -0.211, P = 0.017) and cortical (β = -75.921, 95% CI -151.728 to -0.113, P = 0.050) volumes, and increased ventricular volume (β = 35.175, 95% CI 18.559–51.790, P < 0.001). Moreover, lower baseline levels of Aβ42/Aβ40 were weakly associated with greater worsening in Mini-Mental State Examination and complex associative memory.
CONCLUSIONS: Our findings suggest that the plasma Aβ42/Aβ40 ratio is associated with future amyloid accumulation, brain atrophy, and conversion to prodromal AD in individuals with SCD. This biomarker may help characterize individuals with a higher likelihood of progression and could support earlier and more personalized strategies.
CITATION:
Noelia Fandos ; María Pascual-Lucas ; Leticia Sarasa ; Jose Terencio ; Mª Eugenia Sáez ; Juan Pablo Tartari ; Ángela Sanabria ; Oscar Sotolongo-Grau ; Amanda Cano ; Lluís Tárraga ; Miren Jone Gurruchaga ; Agustín Ruíz ; Xavier Montalban ; Mercè Boada ; Montserrat Alegret ; Marta Marquié ; José Antonio Allué ; on behalf of the FACEHBI study group (2025): Plasma Aβ42/Aβ40 determined by mass spectrometry is associated with longitudinal changes in amyloid accumulation, brain atrophy, and conversion to mild cognitive impairment due to Alzheimer’s disease in individuals with subjective cognitive decline: 5-year follow-up of the FACEHBI cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100465
COST-EFFECTIVENESS ANALYSIS OF BLOOD-BASED BIOMARKER TESTING IN THE DIAGNOSIS OF ALZHEIMER’S DISEASE PATHOLOGY
Yonghong Li, Robert J. Lagier, Michael K. Racke, Yuri A. Fesko
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryOBJECTIVES: We aimed to evaluate the cost-effectiveness of blood-based biomarker (BBM) testing vs amyloid positron emission tomography (PET) in patients with signs and symptoms of cognitive decline in a neurologist/specialist care setting.
METHODS: We constructed a decision-tree model to compare diagnostic outcomes and costs of two testing strategies: BBM testing with confirmatory PET scan vs PET scan alone. Their cost-effectiveness was evaluated from a payer perspective with test performance taken from a clinical study and costs including testing/imaging and physician fees.
RESULTS: When access to PET scans is unlimited, BBM triage testing would identify 98.2 % of PET+ patients with a lower average cost per diagnosis compared with PET scan alone ($8868 vs 10,345 per PET+ diagnosis). In terms of incremental cost-effectiveness, BBM triage testing would save $93,984 for each loss of PET+ diagnosis (9.1 times the average cost per PET+ diagnosis by PET scan). Under limited capacity of PET scans, more test-positive patients could be identified using BBM testing than PET scan alone. When access to PET scans is limited to 50 % of the patients, BBM testing would identify 90.6 % more test-positive patients (at 93 % sensitivity) at an incremental cost-effectiveness ratio of $3484 per gain of positive diagnosis, lower than the average cost of a PET+ diagnosis by PET scan ($10,938).
CONCLUSION: BBM testing, compared with PET scan alone, is more efficient in the utilization of available amyloid PET scans and is cost-effective for assessment of Alzheimer’s disease pathology in patients with signs and symptoms of cognitive decline.
CITATION:
Yonghong Li ; Robert J. Lagier ; Michael K. Racke ; Yuri A. Fesko (2025): Cost-effectiveness analysis of blood-based biomarker testing in the diagnosis of Alzheimer’s disease pathology. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100474
HEAD INJURY/TRAUMATIC BRAIN INJURY AND THE RISK OF DEMENTIA: AN OBSERVATIONAL AND MENDELIAN RANDOMIZATION STUDY
Ziyu Ouyang, Bin Jiao, Xuewen Xiao, Qijie Yang, Yuan Zhu, Lu Shen, Nan Li
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: This study aimed to investigate the link between head injury (HI)/traumatic brain injury (TBI) and dementia risk, as it remains unclear.
METHODS: We examined the associations between HI/TBI-related factors, including the frequency of HIs and the severity of TBI, and the risk of dementia (n = 397,581), as well as neuroimaging outcomes (n = 42,380) using prospective data (50 years at baseline) from the UK Biobank. In the observational analyses, Cox proportional-hazards modeling and logistic regression were used to estimate the associations between factors. Mendelian randomization (MR) was conducted to investigate the underlying causality between TBI (n = 392,423, ncases=19,842) and Alzheimer's disease (AD) (n = 41,944, ncases=21,982).
RESULTS: During the 12.5-year follow-up period, 7524 participants developed dementia. HI and TBI conferred an increased dementia risk (hazard ratio (HR)=1.72, 95 % confidence interval (CI): 1.50–1.97; HR=1.86, 95 % CI: 1.46–2.38, respectively). The risk increased in relation to recurrent HIs (HR=4.05, 95 % CI: 2.24–7.32) or severe TBI (HR=4.50, 95 % CI: 3.18–6.37). Dementia risk was highest during the first 30 months following HI occurrence (HR=2.20, 95 % CI: 1.66–2.92), whereas there was no association after 40 years post-HI. Patients with recurrent HIs also exhibited reduced hippocampal volumes and increased white matter hyperintensity. HI was additionally associated with poorer reasoning ability and longer reaction time. Besides, the MR analysis supported a causal association between TBI and AD (odds ratio (OR)=1.17, 95 % CI: 1.01–1.37).
CONCLUSION: These results imply that HI/TBI is associated with increased dementia risk. Strategies are needed to mitigate the impact of subsequent dementia.
CITATION:
Ziyu Ouyang ; Bin Jiao ; Xuewen Xiao ; Qijie Yang ; Yuan Zhu ; Lu Shen ; Nan Li (2025): Head injury/traumatic brain injury and the risk of dementia: An observational and Mendelian randomization study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100468
PREECLAMPSIA AS A REVERSIBLE RISK FACTOR FOR ALZHEIMER’S DISEASE: A PROSPECTIVE MRI STUDY ON MORPHOLOGICAL CHANGES OF THE CEREBRAL CORTEX AND IMPAIRMENT OF COGNITIVE FUNCTIONS
Yuanyuan Wang, Meng Li, Tao Chen, Yanli Li, Qingqing Wang, Xinyue Zhang, Na Wang, Linfeng Yang, Lingfei Guo, Wenying Nie
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryPURPOSE: To investigate the cross-sectional and longitudinal alterations in cortical thickness and surface area and Cognitive Impairment among patients with preeclampsia.
METHODS: The thickness and surface area of the cerebral cortex were systematically segmented from MRI using the automated cortical segmentation software FreeSurfer, and the corresponding values for each brain region were accurately quantified. Data collection includes the clinical characteristics, serological markers of proteins associated with cognitive function, and cognitive assessments.
RESULTS: Compared with healthy pregnancies, the cortical thicknesses of the right caudal anterior cingulate (R-CACg), right posterior cingulate (R-PoCg), right rostral anterior cingulate (R-RoACg), and right superior frontal (R-SF) in the preeclampsia group exhibited significant alterations. Notably, the change in the R-SF was specific to preeclampsia and was not associated with normal physiological pregnancies. Mediation analysis further confirmed that elevated prepregnancy BMI was directly associated with reduced Symbol Digit Modalities Test scores and indirectly contributed to cognitive decline through an increase in MAP. The cortical thickness of left pars opercularis was identified as a key component in this underlying mechanism. No statistically significant changes in cortical surface area were observed in patients with preeclampsia. Follow-up studies have indicated that cortical thickness alterations in brain regions associated with preeclampsia demonstrate signs of recovery. Among cognitive-related test indicators, only the Auditory Word Learning Test exhibited a statistically significant improvement.
CONCLUSION: The cortical thickness alterations in the R-CACg, R-PoCg, R-RoACg, and R-SF of patients with preeclampsia may represent the structural basis for cognitive impairment. Longitudinal studies have confirmed the neuroplasticity of cortical thickness changes and the potential for recovery from preeclampsia-related memory deficits.
CITATION:
Yuanyuan Wang ; Meng Li ; Tao Chen ; Yanli Li ; Qingqing Wang ; Xinyue Zhang ; Na Wang ; Linfeng Yang ; Lingfei Guo ; Wenying Nie (2025): Preeclampsia as a reversible risk factor for Alzheimer’s disease: A prospective MRI study on morphological changes of the cerebral cortex and impairment of cognitive functions. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100475
THE LIVER AS A METABOLIC AND IMMUNE HUB IN ALZHEIMER’S DISEASE: FROM MECHANISMS TO THERAPEUTIC OPPORTUNITIES
Jiajie Chen, Luyao Wang, Yingying Zhou, Shuoyan Zhao, Qin Chen, Kai Zheng
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryResearch on Alzheimer’s disease (AD) has traditionally focused on the brain. However, emerging evidence indicates that the liver acts as a silent partner in neurodegeneration. As a core hub for metabolic and immune regulation, the liver communicates bidirectionally with the brain via the liver–brain axis, participating in the regulation of various neurophysiological processes, including neurotransmitter regulation, feeding behavior, and cognition. This review summarizes how liver-derived hepatokines, inflammatory mediators, and metabolic products modulate brain function. We highlight that liver dysfunction disrupts the expression of critical molecules—including fibroblast growth factor 21, insulin-like growth factor 1, lipopolysaccharide, and lipocalin-2—thereby driving AD progression by impairing pathological protein clearance, activating neuroinflammation, exacerbating insulin resistance and oxidative stress, and disrupting lipid metabolism. We also discuss the therapeutic potential of targeting the liver–brain axis through lifestyle interventions (e.g., exercise and diet) and pharmacological approaches, to identify novel strategies to delay AD progression. In summary, we underscore the pivotal role of the liver–brain axis in AD pathogenesis and propose it as a promising target for early diagnosis and innovative therapies.
CITATION:
Jiajie Chen ; Luyao Wang ; Yingying Zhou ; Shuoyan Zhao ; Qin Chen ; Kai Zheng (2026): The liver as a metabolic and immune hub in Alzheimer’s disease: From mechanisms to therapeutic opportunities. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100478
CEREBRAL HAEMODYNAMICS AND WHITE MATTER HYPERINTENSITIES: FINDINGS USING NON-INVASIVE BRAIN IMAGING
Ashwati Vipin, James Xiao Yuan Chen, Mervin Tee, Saima Hilal, Yi Jin Leow, Simon Konstandin, Klaus Eickel, Matthias Günther, Jan Petr, Henk JMM Mutsaerts, Nagaendran Kandiah
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: Utilizing non-invasive neuroimaging for characterization of blood brain barrier (BBB) changes and perfusion deficits underlying small vessel disease pathobiology including white matter hyperintensities (WMH) remains largely unexplored.
OBJECTIVES: We examined the underlying haemodynamics of WMH by assessing complex relationships between cerebral blood flow, BBB permeability and WMH burden.
DESIGN, SETTING, PARTICIPANTS: Cross-sectional data from study participants belonging to the community-based Biomarker and Cognition Cohort Study, Singapore was obtained.
MEASUREMENTS: Brain structural and novel non-invasive multi-echo Arterial Spin Labeling data was obtained from 128 participants to derive cerebral blood flow (CBF), arterial transit time (ATT) and BBB time of exchange (Tex).
RESULTS: Neurovascular measures from BBB imaging comprising lower CBF (β=-0.005; p = 0.0139), longer ATT (β=0.644; p = 0.0132) and shorter BBB Tex (β=-0.002; p = 0.0023) were independently associated with higher WMH and higher age-at-visit. Model fit statistics indicated good fit for the structural equation model with a comparative fit index of 0.975 and Standardized Root Mean Square Residual of 0.074. Structural equation modelling revealed CBF (β=0.533; p < 0.001) and ATT (β=-0.254; p = 0.001) as predictors of BBB permeability. Subsequently higher BBB permeability predicted higher WMH burden (β=-0.387; p < 0.001). Additionally, vascular risk factors comprising higher blood pressure and haemoglobinA1C related to lower CBF and shorter BBB Tex.
CONCLUSIONS: Our study highlights that CBF and ATT contribute to BBB permeability, which in turn impacts WMH burden. Vascular risk factors also impact neurovascular measures. These findings add to the growing evidence on the potential role of BBB and perfusion deficits underlying small vessel disease burden.
CITATION:
Ashwati Vipin ; James Xiao Yuan Chen ; Mervin Tee ; Saima Hilal ; Yi Jin Leow ; Simon Konstandin ; Klaus Eickel ; Matthias Günther ; Jan Petr ; Henk JMM Mutsaerts ; Nagaendran Kandiah (2026): Cerebral haemodynamics and white matter hyperintensities: findings using non-invasive brain imaging. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100479
POTENTIAL ROLE OF MRI TO OPTIMIZE CLINICAL TRIAL DESIGN FOR PROGRESSIVE SUPRANUCLEAR PALSY AND CORTICOBASAL DEGENERATION
Jesús García-Castro, Lawren VandeVrede, Michael C. Donohue, Lídia Vaqué-Alcázar, Sara Rubio-Guerra, Judit Selma-González, Hilary W. Heuer, Alejandra O. Morcillo-Nieto, María Franquesa, Oriol Dols-Icardo, Alexandre Bejanin, Olivia Belbin, Juan Fortea, Daniel Alcolea, Maria Carmona-Iragui, Carla Abdelnour, Isabel Barroeta, Miguel Santos-Santos, María Belen Sánchez Saudinós, Isabel Sala, Alberto Lleó, Maria Luisa Gorno-Tempini, Maria Luisa Mandelli, Rema Raman, Anne-Marie A Wills, Eden Barragan, Irene Litvan, Brad Boeve, Brad Dickerson, Murray Grossman, Edward D. Huey, David J. Irwin, Alex Pantelyat, Carmela Tartaglia, Julio C. Rojas, Adam L. Boxer, Ignacio Illán-Gala, on behalf of theFour Repeat Tau Neuroimaging Initiative (4RTNI) and the AL108-231 Investigators
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are 4–repeat tauopathies (4RT) presenting with overlapping syndromes. Imperfect clinicopathological associations increase sample-size demands in clinical trials. We test whether MRI can enrich trials for PSP/CBD and provide sensitive MRI-based outcome measures.
METHODS: Longitudinal cohort analysis including participants from the 4 Repeat Tauopathy Neuroimaging Initiative (4RTNI) and phase 2/3 Davunetide trial (DAV). An MRI model trained on autopsy-confirmed cases predicted PSP (MRI-PSP) or CBD (MRI-CBD); corticobasal syndrome (CBS) with positive Alzheimer’s biomarkers was reclassified. Clinical scales and MRI-derived thickness/volume were analyzed with linear mixed-effects models. We derived data-driven MRI-signatures (optimal regional combinations) to minimize required trial sample sizes.
RESULTS: 206 participants from 4RTNI (n = 106 with Richardson’s syndrome [RS], CBS, or nonfluent/agrammatic primary progressive aphasia [nfvPPA]) and DAV (n = 100 with RS). In 4RTNI, 49 participants were predicted MRI-PSP and 43 MRI-CBD. 76% of MRI-PSP had RS, 24% had CBS/nfvPPA; 66% of MRI-CBD had CBS. PSP and CBD signatures shared midbrain/pontine atrophy but differed in cortical involvement. PSP signature correlated strongly with 12-month change on the PSP Rating Scale (β = –0.59, p < 0.001). MRI-based signatures reduced the estimated sample sizes required to detect 30% reduction in progression over 12-months by 50% for MRI-PSP and 87% for MRI-CBD, compared with clinical outcomes. In DAV, feasibility was replicated.
CONCLUSION: MRI-derived models can identify PSP or CBD with high accuracy, and MRI-based signatures track progression more sensitively than established clinical outcomes. Incorporating these tools into therapeutic trial design could reduce sample sizes and enable more inclusive disease-modifying trials for 4RT.
CITATION:
Jesús García-Castro ; Lawren VandeVrede ; Michael C. Donohue ; Lídia Vaqué-Alcázar ; Sara Rubio-Guerra ; Judit Selma-González ; Hilary W. Heuer ; Alejandra O. Morcillo-Nieto ; María Franquesa ; Oriol Dols-Icardo ; Alexandre Bejanin ; Olivia Belbin ; Juan Fortea ; Daniel Alcolea ; Maria Carmona-Iragui ; Carla Abdelnour ; Isabel Barroeta ; Miguel Santos-Santos ; María Belen Sánchez Saudinós ; Isabel Sala ; Alberto Lleó ; Maria Luisa Gorno-Tempini ; Maria Luisa Mandelli ; Rema Raman ; Anne-Marie A Wills ; Eden Barragan ; Irene Litvan ; Brad Boeve ; Brad Dickerson ; Murray Grossman ; Edward D. Huey ; David J. Irwin ; Alex Pantelyat ; Carmela Tartaglia ; Julio C. Rojas ; Adam L. Boxer ; Ignacio Illán-Gala ; on behalf of theFour Repeat Tau Neuroimaging Initiative (4RTNI) and the AL108-231 Investigators (2026): Potential role of MRI to optimize clinical trial design for progressive supranuclear palsy and corticobasal degeneration. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100486
ASSOCIATION OF PLASMA P-TAU AND P-TAU/AΒ RATIO WITH ALZHEIMER\'S PATHOLOGY
Xuhui Chen, Mingxing Jiang, Laihong Zhang, Jiayi Zhu, Anqi Li, Zhengbo He, Xin Zhou, Yalin Zhu, Chen Zhang, Cong Wang, Mingxu Li, Yiying Wang, Xinyue Ma, Binhui Liu, Rong Ma, Yipeng Jin, Xiang Fan, Zhen Liu, Tengfei Guo, Yong-An Sun, Guoyu Lan
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: Plasma phosphorylated tau (p-tau) and β-amyloid (Aβ) are promising biomarkers for Alzheimer’s disease (AD). However, it remains unclear whether combining p-tau with Aβ provides better predictive performance than using p-tau alone.
OBJECTIVES: To evaluate the predictive utility of plasma p-tau and Aβ combinations for AD-related pathology, brain atrophy, and cognitive decline.
DESIGN, SETTING, AND PARTICIPANTS: This study included 352 participants from the Greater-Bay Area Healthy Aging Brain Study (GHABS) cohort in China, classified into 227 Aβ-negative and 125 Aβ-positive individuals.
MEASUREMENTS: Participants underwent Aβ positron emission tomography (PET) and plasma biomarker assessments. Plasma concentrations of p-tau181, p-tau217, p-tau231, Aβ42, and Aβ40 were quantified on the Quanterix HD-X and Lumipulse G1200 platform.
RESULTS: Among the individual plasma p-tau variants, p-tau217 consistently outperformed p-tau181 and p-tau231. The combination of p-tau biomarkers (p-tau181, p-tau217, and p-tau231) with Aβ42 or the Aβ42/40 ratio further improved discrimination between Aβ+/CU (cognitively unimpaired) and Aβ-/CU individuals. Both p-tau/Aβ42 and p-tau/(Aβ42/40) exhibited slightly stronger or comparable associations with Aβ PET burden, baseline and longitudinal measures of hippocampal atrophy, AD-typical cortical thinning, and cognitive decline, relative to p-tau alone.
CONCLUSIONS: The head-to-head comparisons indicate that p-tau217 is the most robust biomarker among the variants tested, and p-tau/Aβ ratios perform comparably or slightly better than p-tau alone in reflecting AD pathology, potentially providing complementary information for early detection and monitoring of disease progression.
CITATION:
Xuhui Chen ; Mingxing Jiang ; Laihong Zhang ; Jiayi Zhu ; Anqi Li ; Zhengbo He ; Xin Zhou ; Yalin Zhu ; Chen Zhang ; Cong Wang ; Mingxu Li ; Yiying Wang ; Xinyue Ma ; Binhui Liu ; Rong Ma ; Yipeng Jin ; Xiang Fan ; Zhen Liu ; Tengfei Guo ; Yong-An Sun ; Guoyu Lan (2026): Association of plasma p-tau and p-tau/Aβ ratio with Alzheimer's pathology. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100472
IDENTIFYING RISK FACTORS OF YOUNG-ONSET DEMENTIA AND EVALUATING EVIDENCE HIERARCHY: A META-ANALYSIS AND UMBRELLA REVIEW
Jiayu Zhang, Dandan Yang, Jian Liang, Yin Hu, Liping Rao, Jun Huang, Qijun Wu, Bo Jiang
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryBACKGROUND: Young-onset dementia (YOD) directly affects the working-age population. The premature onset of dementia intensifies peer caregiving responsibilities and diverts medical and nursing resources. While modifiable risk factors for late-onset dementia have been well established, uncertainty remains regarding the applicability of these findings to YOD. We aim to identify modifiable risk factors for YOD and evaluate the strength of evidence.
METHODS: We searched PubMed, Embase, Web of Science, and Ovid Medline from inception to 22 May 2025 for epidemiological studies on non-genetic risk factors for YOD. We used random-effects meta-analyses with the inverse variance method to pool relative risks (RRs) and 95% confidence intervals (CIs). A series of statistical tests were designed to classify the strength of evidence of significant associations as convincing, highly suggestive, suggestive, or weak evidence.
RESULTS: From 25,731 initial and 2289 updated search records, 36 studies examining 31 non-genetic risk factors for YOD were identified. Of the 31 associations examined, 21 were nominally statistically significant at P < 0.05 based on random-effects models. Prior stroke was convincingly associated with an increased risk of YOD. Evidence of association was highly suggestive for alcohol use disorders, diabetes, depression, mood disorders, Parkinson's disease, multiple sclerosis, use of antidepressants/antipsychotics, and asthma.
CONCLUSION: We found that the risk of dementia in young individuals may be closely related to neuropsychiatric symptoms and clinical alcohol disorders. Future research should further validate these findings and explore intervention strategies to reduce dementia risk in younger individuals.
CITATION:
Jiayu Zhang ; Dandan Yang ; Jian Liang ; Yin Hu ; Liping Rao ; Jun Huang ; Qijun Wu ; Bo Jiang (2025): Identifying risk factors of young-onset dementia and evaluating evidence hierarchy: a meta-analysis and umbrella review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100467
ASSOCIATION BETWEEN PLASMA METAL ELEMENT PROFILES AND COGNITIVE IMPAIRMENT IN OCCUPATIONALLY ALUMINUM-EXPOSED WORKERS AT A LARGE ALUMINUM PLANT IN NORTHERN CHINA
Xin Guo, Fangyu Gao, Mujia Li, Baolong Pan, Feng Gao, Shanshan Wang, Jingsi Zhang, Xiaoting Lu, Jing Song, Linping Wang, Huifang Zhang, Qiao Niu
J Prev Alz Dis 2026;3(13)
Show summaryHide summaryThis study explored the association between plasma levels of multiple metals and cognitive impairment (CI) in 455 aluminum electrolysis workers from a northern Chinese plant, divided into CI (256) and control (199) groups by MoCA scores. Using inductively coupled plasma mass spectrometry, 11 metals were measured, with analyses via conditional logistic regression,generalized linear models (GLM), Bayesian kernel machine regression (BKMR), and age stratification (40 years). Plasma aluminum (Al), lead (Pb), lithium (Li), manganese, cobalt, and copper were significantly higher in the CI group (all P < 0.05), while zinc showed no difference. Single-element analysis found Al, Pb, and Li negatively correlated with MoCA total and subscores (e.g., visuospatial function; P < 0.05), and zinc positively correlated with attention (β = 1.10, P < 0.05). BKMR confirmed metal mixtures above the 25th percentile reduced MoCA scores (β = -0.875, 95 % CI: -1.379 to -0.371), with Al, Pb, and Li as key contributors (PIP > 0.6). Subgroup analysis showed Al primarily affected those <40, while Pb had greater impact in those >40. Findings indicate elevated Al, Pb, and Li associate with higher CI risk, metal mixtures synergistically exacerbate impairment, and age modifies these effects, aiding occupational cognitive impairment prevention.
CITATION:
Xin Guo ; Fangyu Gao ; Mujia Li ; Baolong Pan ; Feng Gao ; Shanshan Wang ; Jingsi Zhang ; Xiaoting Lu ; Jing Song ; Linping Wang ; Huifang Zhang ; Qiao Niu (2025): Association between plasma metal element profiles and cognitive impairment in occupationally aluminum-exposed workers at a large aluminum plant in northern China. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100470