Ahead of print articles
COMBINED EFFECT OF ANXIETY DISORDER AND INSOMNIA ON THE RISK OF INCIDENT ADRD DIAGNOSIS
SangNam Ahn, Joanne Salas, Jinmyoung Cho, Jeffrey F. Scherrer
Show summaryHide summary
BACKGROUND: Anxiety disorders and insomnia are common modifiable conditions in older adults, but their independent and combined effects on the risk of incident Alzheimer’s disease and related dementias (ADRD) remain unclear.
OBJECTIVES: To estimate the independent and combined associations of anxiety disorders and insomnia with the risk of incident ADRD.
DESIGN: Retrospective cohort study using an intention-to-treat approach with a 10-year follow-up period (2014–2023).
SETTING: De-identified electronic health record (EHR) data from 70 participating healthcare organizations within the TriNetX Research Network.
PARTICIPANTS: Adults aged ≥50 years without prior dementia who had regular ambulatory care during a three-year baseline period (n = 1,868,790).
MEASUREMENTS: Anxiety and insomnia were identified using ICD-based algorithms and categorized into four exposure groups: neither condition, anxiety only, insomnia only, and both. Incident ADRD was defined by two or more diagnostic codes within 12 months. Entropy balancing controlled for confounding, and weighted Cox proportional hazards models estimated hazard ratios (HRs).
RESULTS: At baseline, 4.1% had anxiety only, 3.8% had insomnia only, and 1.1% had both. Over follow-up, 2.3% developed ADRD. In weighted models, insomnia alone (HR: 1.12; 95% CI: 1.06–1.19), anxiety alone (HR: 1.49; 95% CI: 1.39–1.60), and co-occurring anxiety and insomnia (HR: 1.31; 95% CI: 1.06–1.62) were each associated with higher ADRD risk compared with neither condition. No significant effect modification by age, sex, or race was observed.
CONCLUSIONS: Anxiety and insomnia independently increase ADRD risk, though insomnia's contribution is very modest compared to the primary association demonstrated by anxiety. Co-occurrence does not confer additional risk beyond anxiety alone. Clinically, routine screening and treatment of anxiety and sleep disturbances represent actionable, broadly applicable strategies for ADRD prevention and healthy cognitive aging.
CITATION:
SangNam Ahn ; Joanne Salas ; Jinmyoung Cho ; Jeffrey F. Scherrer (2025): Combined effect of anxiety disorder and insomnia on the risk of incident ADRD diagnosis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100621
PLASMA BRAIN-DERIVED P-TAU217 OUTPERFORMS OTHER P-TAU SPECIES IN DETECTING ABNORMAL BRAIN AMYLOID IN AN ASIAN COHORT OF OLDER PEOPLE WITH CEREBROVASCULAR DISEASE BURDEN
Joyce R. Chong, Saima Hilal, Narayanaswamy Venketasubramanian, Michael Schöll, Nicholas J. Ashton, Henrik Zetterberg, Christopher P. Chen, Mitchell K.P. Lai
Show summaryHide summary
BACKGROUND: Plasma brain derived-p-Tau217 (BD-p-Tau217) may outperform total-p-Tau217 in detecting brain amyloid burden and warrants evaluation.
OBJECTIVES: To perform head-to-head comparison of plasma BD- as well as total-p-Tau181, p-Tau217 and p-Tau231 for detecting beta-amyloid positivity (Aβ+), evaluate reference ranges for Aβ+, and assess the prognostic utility of BD-p-Tau217 reference ranges.
DESIGN: Observational study.
SETTING: Participants recruited from memory clinics and the community in Singapore.
PARTICIPANTS: 213 participants, including 44 cognitively normal, 107 cognitively impaired no dementia, and 62 dementia (mean [SD] age, 73 [1] years; 121 females).
MEASUREMENTS: Amyloid status (Aβ- [n = 139] vs Aβ+ [n = 74]) was determined by positron emission tomography (PET). Plasma BD-p-Tau and total-p-Tau were measured using the NULISAseq™ CNS Disease Panel 120. The diagnostic performance for detecting Aβ+, reference ranges (three-range: 95% specificity/95% sensitivity); binary: maximizing Youden index), and the prognostic performance of p-Tau biomarkers were evaluated.
RESULTS: Plasma BD-p-Tau217 (AUC = 0.965) outperformed other BD- and total-p-Tau species in detecting PET Aβ+ (AUC = 0.823–0.937; all p ≤ 0.008). Using a three-range reference, BD-p-Tau217 achieved positive predictive value (PPV) and negative predictive value (NPV) of 90% and 97%, respectively. Proportion of participants in the intermediate-risk group was 7% (n = 14). Applying a binary reference, BD-p-Tau217 achieved both a specificity and sensitivity of 92%, with PPV and NPV of 86% and 96%, respectively. BD-p-Tau217-derived high-risk group exhibited faster cognitive decline than the low-risk group.
CONCLUSIONS: Risk stratification for PET Aβ+ based on plasma BD-p-Tau217 suggests superior diagnostic and prognostic utility, warranting further validation.
CITATION:
Joyce R. Chong ; Saima Hilal ; Narayanaswamy Venketasubramanian ; Michael Schöll ; Nicholas J. Ashton ; Henrik Zetterberg ; Christopher P. Chen ; Mitchell K.P. Lai (2025): Plasma brain-derived p-Tau217 outperforms other p-Tau species in detecting abnormal brain amyloid in an Asian cohort of older people with cerebrovascular disease burden. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100615
THE GROWING BURDEN OF DEMENTIA IN ASIA: COMPARATIVE INSIGHTS FROM JAPAN, CHINA, AND INDIA
Chen Zhang, Xuhui Chen, Yongan Sun
Show summaryHide summary
BACKGROUND: Alzheimer's disease and other dementias (ADODs) are increasingly becoming a major public health concern in rapidly ageing Asia. We compared the disease burden across Japan, China, and India at different demographic stages.
DESIGN: The Global Burden of Disease Study of 2023 was used to analyze the incidence, prevalence, mortality, and disability-adjusted life years (DALYs) in 1990–2023. Decomposition analysis identified drivers of DALYs trends. DALYs associated risk factors were quantified. The Auto-Regressive Integrated Moving Average model was used to predict future disease burden.
RESULTS: In 2023, China had the highest absolute burden, with age-standardized incidence and prevalence rates of 156.63 (95% uncertainty interval [UI]: 136.58–175.49) and 918.83(95% UI: 784.59–1,058.24) per 100,000, respectively. Japan recorded the highest age-standardized mortality rate (31.25 [8.47–71.42] per 100,000). India had the highest annual increase in mortality and DALYs, with estimated annual percentage changes of 0.91 (95% confidence interval [95% CI] 0.80–1.03) and 0.51 (0.45–0.56), respectively. Decomposition analysis revealed distinct drivers: Japan was dominated by epidemiological changes; China was driven by both aging and epidemiological changes; India was mainly due to population growth and epidemiological changes. Ambient particulate matter was the leading risk factor across all countries, though India faced a unique household air pollution burden. DALYs are predicted to increase in all three countries significantly by 2038.
CONCLUSIONS: The ADODs burden remains substantial, driven by distinct demographic and epidemiological factors in Japan, China, and India. Tailored strategies for prevention and management are essential to address the growing burden.
CITATION:
Chen Zhang ; Xuhui Chen ; Yongan Sun (2025): The growing burden of dementia in Asia: Comparative insights from Japan, China, and India. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100614
DIAGNOSTIC PERFORMANCE OF AN AUTOMATED PLASMA P-TAU217 CHEMILUMINESCENT ASSAY FOR DETECTING AΒ PATHOLOGY IN A CHINESE MEMORY CLINIC COHORT
Shuai Chen, Feng-Yu Wang, Rong Li, Chang Fu, Jing-Yu Shao, Yu Shen, Kai Ma, Xiao-Di Hao, Lin Cao, Jun-Ling Xu, Jie-Wen Zhang
Show summaryHide summary
BACKGROUND: Blood-based biomarkers have emerged as promising tools for detecting Alzheimer’s disease (AD) pathology, but validation of automated plasma assays in Chinese clinical populations remains limited. This study evaluated the diagnostic performance of a fully automated chemiluminescent plasma biomarker assay for detecting amyloid-β (Aβ) pathology in a Chinese memory clinic cohort under different pre-analytical conditions.
METHODS: We enrolled 409 cognitively impaired participants from a single-center memory clinic, using amyloid-β positron emission tomography (Aβ-PET) as the reference standard. Plasma samples were analyzed under two pre-analytical conditions: frozen batch-processed samples from a historical cohort (n = 198) and freshly collected samples analyzed in real time in a prospective cohort (n = 211). Additionally, 95 participants underwent tau-PET imaging. Six plasma biomarkers were quantified using the Vazyme® AD Assay.
RESULTS: Across cohorts, p-tau217, p-tau217/Aβ42 ratio, and NfL/p-tau217 ratio consistently achieved excellent diagnostic performance (AUCs 0.92–0.95), followed by p-tau181 (AUCs 0.86–0.90). GFAP (AUCs 0.82–0.83) and the Aβ42/40 ratio (AUCs 0.76–0.81) showed moderate discriminative performance. Plasma p-tau217 alone achieved diagnostic accuracy comparable to composite biomarker models. A dual cut-point strategy reduced the indeterminate zone to <30%, with positive predictive values of 0.97–0.99 and negative predictive values of 0.86–0.87. Plasma p-tau217 was also significantly associated with tau-PET burden in both meta-temporal and neocortical regions (P < 0.001).
CONCLUSION: This automated chemiluminescent plasma biomarker assay demonstrated high diagnostic accuracy for detecting Aβ pathology in a Chinese memory clinic cohort under different pre-analytical conditions. The findings support its potential utility as a practical blood-based biomarker approach in specialized clinical settings, while further multicenter studies are needed to confirm its generalizability across broader populations and healthcare environments.
CITATION:
Shuai Chen ; Feng-Yu Wang ; Rong Li ; Chang Fu ; Jing-Yu Shao ; Yu Shen ; Kai Ma ; Xiao-Di Hao ; Lin Cao ; Jun-Ling Xu ; Jie-Wen Zhang (2025): Diagnostic performance of an automated plasma p-tau217 chemiluminescent assay for detecting Aβ pathology in a Chinese memory clinic cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100613
MULTIMODAL BIOMARKER CHARACTERIZATION OF AMNESTIC OBJECTIVE SUBTLE COGNITIVE DECLINE IN AGING AND PRECLINICAL ALZHEIMER’S DISEASE
David López-Martos, Raffaele Cacciaglia, Marc Suárez-Calvet, Gemma Salvadó, Mahnaz Shekari, Armand González-Escalante, Marta Milà-Alomà, Anna Brugulat-Serrat, Carolina Minguillon, Matteo Tonietto, Edilio Borroni, Gregory Klein, Clara Quijano-Rubio, Gwendlyn Kollmorgen, Henrik Zetterberg, Kaj Blennow, Juan Domingo Gispert, Oriol Grau-Rivera, Gonzalo Sánchez-Benavides, ALFA study
Show summaryHide summary
BACKGROUND: The objective of this study was to provide a multimodal biomarker characterization of amnestic objective subtle cognitive decline (obj-SCD) in aging and preclinical Alzheimer’s disease (AD).
METHODS: Prospective observational study; data from the Alzheimer’s and Families+ (ALFAs+) cohort, including cognitively unimpaired (CU) individuals with available baseline CSF biomarkers (normal or AD continuum profiles) and longitudinal neuropsychological assessment (2 time points, 3-year follow-up). Amnestic obj-SCD was defined using robust longitudinal neuropsychological references with multivariate base rate thresholds of significant decline (Free and Cued Selective Reminding Test, Memory Binding Test, Wechsler Memory Scale IV: Logical Memory). Study outcomes included plasma p-tau217, NfL, and GFAP; CSF p-tau181/Aβ42, NfL, and GFAP; Aβ and tau PET; and MRI Grey Matter volume (GMv). The associations of amnestic obj-SCD with fluid (plasma and CSF) and neuroimaging biomarkers (PET and GMv) were evaluated using mixed-effects and voxel-wise linear regression models, respectively.
RESULTS: 350 CU individuals were included (mean age 61 years; 60% female; mean education 14 years; 35% CSF Aβ-positive). Amnestic obj-SCD was identified in 10% of the sample, associated with greater AD pathology (higher plasma p-tau217, CSF p-tau181/Aβ42, global Aβ PET, medial temporal tau PET), neurodegeneration (higher plasma and CSF NfL, reduced GMv in cingulate cortex, longitudinal GMv reductions in hippocampus) and inflammation (higher plasma and CSF GFAP, longitudinal GMv increases in neocortical brain regions).
DISCUSSION: These findings highlight the need for standardized clinical staging criteria to enhance early detection and risk stratification in aging and preclinical AD.
CITATION:
David López-Martos ; Raffaele Cacciaglia ; Marc Suárez-Calvet ; Gemma Salvadó ; Mahnaz Shekari ; Armand González-Escalante ; Marta Milà-Alomà ; Anna Brugulat-Serrat ; Carolina Minguillon ; Matteo Tonietto ; Edilio Borroni ; Gregory Klein ; Clara Quijano-Rubio ; Gwendlyn Kollmorgen ; Henrik Zetterberg ; Kaj Blennow ; Juan Domingo Gispert ; Oriol Grau-Rivera ; Gonzalo Sánchez-Benavides ; ALFA study (2025): Multimodal biomarker characterization of amnestic objective subtle cognitive decline in aging and preclinical Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100612
EFFICACY AND SAFETY OF DONANEMAB IN THE EUROPEAN ELIGIBLE POPULATION: TRAILBLAZER-ALZ 2 POST-HOC ANALYSES
Frank Jessen, Grazia Dell’Agnello, Jennifer A. Zimmer, Christophe Sapin, Sascha Dichter, Erin Doty, Stéphane Epelbaum, Cynthia D. Evans, Paula M. Hauck, Rashna Khanna, Dawn A. Brooks, John R. Sims, Federica Agosta
Show summaryHide summary
BACKGROUND: In the European Union (EU), donanemab is indicated in adults with early symptomatic Alzheimer’s disease who are apolipoprotein E ε4 non-carriers or heterozygotes. Among these, patients without superficial siderosis at baseline, uncontrolled hypertension, or anticoagulant use are eligible.
OBJECTIVE: To assess efficacy and safety of donanemab in the EU-eligible population.
METHODS: A post-hoc conservative hybrid imputation method was implemented for clinical efficacy analyses during the TRAILBLAZER-ALZ 2 placebo-controlled period. In the 78-week long-term extension (LTE) participants in the early-start (randomised to donanemab) and delayed-start (randomised to placebo with donanemab initiation during the LTE) groups were compared to a propensity-weighted external control. Participants were switched to placebo after meeting amyloid-based treatment course completion criteria.
RESULTS: By 76 weeks, donanemab-treated participants in the EU-eligible population had a mean Clinical Dementia Rating Scale (CDR)-Sum of Boxes change from baseline difference from placebo of -0.7 points (95% confidence interval, -1.0, -0.4) and a 40.3% lower risk of disease progression to the next stage (per CDR-Global score). Treatment benefit increased over 154 weeks for non-carriers and heterozygotes, including those meeting treatment course completion criteria by 52 or 76 weeks. In the placebo-controlled period, 119 (19.5%) and 49 (8.0%) donanemab-treated eligible participants experienced amyloid-related imaging abnormalities-edema/effusion and infusion-related reactions, respectively. Safety findings were similar among donanemab-treated participants in the placebo-controlled period and LTE delayed-start group.
CONCLUSIONS: Consistent with previous TRAILBLAZER-ALZ 2 and LTE findings, donanemab significantly slowed disease progression compared to controls with a manageable safety profile in non-carriers and heterozygotes.
CITATION:
Frank Jessen ; Grazia Dell’Agnello ; Jennifer A. Zimmer ; Christophe Sapin ; Sascha Dichter ; Erin Doty ; Stéphane Epelbaum ; Cynthia D. Evans ; Paula M. Hauck ; Rashna Khanna ; Dawn A. Brooks ; John R. Sims ; Federica Agosta ; Alzheimer’s Disease Neuroimaging Initiative (ADNI) (2025): Efficacy and safety of donanemab in the European eligible population: TRAILBLAZER-ALZ 2 post-hoc analyses. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100605
SUBJECTIVE COGNITION TRAJECTORIES, ALZHEIMER BIOMARKERS, AND INCIDENT MILD COGNITIVE IMPAIRMENT
Elizabeth Kuhn, Luca Kleineidam, Melina Stark, Oliver Peters, Julian Hellmann-Regen, Lukas Preis, Daria Gref, Josef Priller, Eike Jakob Spruth, Maria Gemenetzi, Anja Schneider, Klaus Fliessbach, Jens Wiltfang, Claudia Bartels, Niels Hansen, Ayda Rostamzadeh, Emrah Düzel, Wenzel Glanz, Enise Incesoy, Katharina Buerger, Daniel Janowitz, Sophia Stöcklein, Robert Perneczky, Boris-Stephan Rauchmann, Stefan J. Teipel, Ingo Kilimann, Christoph Laske, Sebastian Sodenkamp, Annika Spottke, Marie Kronmüller, Sandra Roeske, Frederic Brosseron, Alfredo Ramirez, Matthis Synofzik, Matthias C. Schmid, Frank Jessen, Michael Wagner, Alzheimer’s Disease Neuroimaging Initiative, DELCODE study group
Show summaryHide summary
BACKGROUND: Subjective cognitive decline is common in older adults and may represent an early clinical signal along the Alzheimer’s disease continuum. The clinical relevance of longitudinal changes in subjective cognitive decline remains unclear.
OBJECTIVES: To determine whether trajectories of self- or study partner-reported cognitive decline predict progression to mild cognitive impairment and reflect Alzheimer’s disease-specific biological patterns.
DESIGN, SETTING, PARTICIPANTS: Data were pooled from two observational cohorts. Cognitively unimpaired participants with baseline amyloid status, repeated assessments of subjective cognitive decline, and clinical follow-up were included. The study included 770 participants with a median follow-up of 5.0 years (interquartile range 4.0–7.0).
MEASUREMENTS: Subjective cognitive decline was assessed using the Everyday Cognition questionnaire completed by participants and study partners. Linear mixed-effects models examined associations with amyloid status and progression to mild cognitive impairment. Cox proportional hazards models tested whether one-year changes predicted progression.
RESULTS: Amyloid-positive participants and those who progressed to mild cognitive impairment showed steeper increases in self- and study partner-reported cognitive difficulties over time. Among amyloid-positive participants, only increases in study partner-report differentiated progressors from non-progressors. One-year increases in study partner-report predicted a higher risk of mild cognitive impairment compared with unchanged scores (hazard ratio 3.24; 95% confidence interval 1.73–6.07]), with effects confined to amyloid-positive participants.
CONCLUSIONS: Short-term increases in study partner-reported cognitive difficulties identify amyloid-positive cognitively unimpaired older adults at increased risk of near-term progression to mild cognitive impairment. Longitudinal monitoring using study partner reports may provide a low-burden and clinically relevant approach for early risk stratification and surveillance in aging populations.
CITATION:
Elizabeth Kuhn ; Luca Kleineidam ; Melina Stark ; Oliver Peters ; Julian Hellmann-Regen ; Lukas Preis ; Daria Gref ; Josef Priller ; Eike Jakob Spruth ; Maria Gemenetzi ; Anja Schneider ; Klaus Fliessbach ; Jens Wiltfang ; Claudia Bartels ; Niels Hansen ; Ayda Rostamzadeh ; Emrah Düzel ; Wenzel Glanz ; Enise Incesoy ; Katharina Buerger ; Daniel Janowitz ; Sophia Stöcklein ; Robert Perneczky ; Boris-Stephan Rauchmann ; Stefan J. Teipel ; Ingo Kilimann ; Christoph Laske ; Sebastian Sodenkamp ; Annika Spottke ; Marie Kronmüller ; Sandra Roeske ; Frederic Brosseron ; Alfredo Ramirez ; Matthis Synofzik ; Matthias C. Schmid ; Frank Jessen ; Michael Wagner ; for theAlzheimer’s Disease Neuroimaging Initiative ⁎and theDELCODE study group (2025): Subjective cognition trajectories, Alzheimer biomarkers, and incident mild cognitive impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100609
MAPPING THE NATURE, TYPE, AND ASSOCIATION NETWORK OF SAFETY INCIDENTS AMONG INDIVIDUALS WITH COGNITIVE IMPAIRMENT IN CHINA: A LARGE-SCALE MULTICENTER CROSS-SECTIONAL STUDY
Ying Zhou, Guoping Peng, Zhengluan Liao, Huayan Liu, Jun Liu, Wang Liao, Qiumin Qu, Jingping Shi, Jieli Geng, Nan Zhi, Wenwei Cao, Yaying Song, Yang Zhang, Xiaohong Wang, Lin Wang, Yuan Zhu, Yan Zhou, Huali Wang, Yongan Sun, Rujing Ren, Hengge Xie, Gang Wang, representing ADC
Show summaryHide summary
BACKGROUND: Patient safety critically influences both quality of life and disease progression in older adults with cognitive impairment, yet large-scale multicenter data remain scarce. This study aims to systematically analyze the types of safety incidents experienced by patients with Alzheimer’s disease and related cognitive impairments, and explore the network associations of different safety incidents.
METHODS: Initiated by the Alzheimer's Disease China (ADC), this survey recruited 1057 older individuals with Alzheimer’s and related cognitive impairments, along with their families, across 31 provinces, autonomous regions, and municipalities. The safety incidents evaluated in this study included falls, getting lost, medication errors, verbal aggression, physical aggression, household fire, aspiration, and choking. Incidence rates for overall and specific safety incidents were calculated. Correlation analyses and network analysis were performed to examine relationships between safety incidents.
RESULTS: A high proportion (73.5%) of participants reported at least one safety incident in the past year, with over one-third (36.0%) experiencing three or more concurrent incidents. Medication errors (55.9%) and verbal aggression (39.6%) were most frequent, followed by falls (32.5%) and physical aggression (22.7%). Incidence rates varied significantly by cognitive impairment stage, care setting, and geographic region. Network analysis highlighted medication errors and getting lost as central nodes bridging other incidents.
CONCLUSIONS: This study reveals an alarmingly high incidence of safety incidents among cognitively impaired patients, affecting their physical, psychological, and familial well-being. A collaborative, multidisciplinary effort involving healthcare professionals, family caregivers, fire and police emergency responders, and public health policymakers is essential to develop individualized safety strategies aligned with patient needs and contextual considerations.
CITATION:
Ying Zhou ; Guoping Peng ; Zhengluan Liao ; Huayan Liu ; Jun Liu ; Wang Liao ; Qiumin Qu ; Jingping Shi ; Jieli Geng ; Nan Zhi ; Wenwei Cao ; Yaying Song ; Yang Zhang ; Xiaohong Wang ; Lin Wang ; Yuan Zhu ; Yan Zhou ; Huali Wang ; Yongan Sun ; Rujing Ren ; Hengge Xie ; Gang Wang ; representing ADC (2025): Mapping the nature, type, and association network of safety incidents among individuals with cognitive impairment in China: a large-scale multicenter cross-sectional study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100606
IDENTIFICATION OF A CD44-DEPENDENT CONTROL OF ASTROCYTIC AUTOPHAGIC ACTIVITY IN ALZHEIMER’S DISEASE
Haiyan Wang, Ying Long, Yu Tang, Lijie Duan, Zijie Wang, Shuzhen Zhang, Yanqing Yin, Jiawei Zhou, Wenjuan Wu, Chunjiu Zhong
Show summaryHide summary
BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. Despite extensive research, the precise molecular mechanisms driving AD pathogenesis remain incompletely understood. This study sought to identify robust molecular targets and cellular basis underlying AD progression.
METHODS: We performed a systematic analysis of cross-regional transcriptomic datasets from AD patients, integrating differential expression analysis across 14 Gene Expression Omnibus (GEO) datasets with cross-regional intersection mapping. Single-nucleus RNA sequencing (snRNA-seq) was employed to resolve cell-type-specific expression patterns. Furthermore, cellular communication analysis and functional enrichment of astrocyte-specific genes were conducted. The biological role of the identified candidate was validated in vitro using Aβ42 oligomer-treated primary astrocytes via siRNA-mediated knockdown and plasmid-driven overexpression, with autophagic activity assessed through LC3-II and p62 expression.
RESULTS: The transmembrane glycoprotein receptor CD44 was identified as consistently upregulated across AD-vulnerable brain regions, including the temporal cortex, frontal cortex, entorhinal cortex, and hippocampus. snRNA-seq analysis identified this upregulation primarily to astrocytes. Intercellular signaling analysis indicated that the CD44-SPP1 axis enhanced astrocyte-glial crosstalk. Functional enrichment analysis linked astrocytic CD44 to the modulation of autophagy pathways. In vitro experiments demonstrated that CD44 knockdown promoted autophagic activation (increased LC3-II and decreased p62), whereas CD44 overexpression suppressed autophagic activity.
CONCLUSION: Our findings establish CD44 as a pivotal regulator of astrocytic autophagy in AD, highlighting its potential as a novel therapeutic target.
CITATION:
Haiyan Wang ; Ying Long ; Yu Tang ; Lijie Duan ; Zijie Wang ; Shuzhen Zhang ; Yanqing Yin ; Jiawei Zhou ; Wenjuan Wu ; Chunjiu Zhong (2025): Identification of a CD44-dependent control of astrocytic autophagic activity in Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100601
REDUCTIONS IN NEUROPSYCHIATRIC SYMPTOMS AFTER LECANEMAB TREATMENT AND THEIR ASSOCIATIONS WITH IMAGING MARKERS OF Β-AMYLOID CLEARANCE
Yaping Yan, Daoyan Hu, Linlin Kong, Kaicheng Li, Jun Su, Yingzhe Wu, Hongwei Zhan, Hong Zhang, Yidan Sun, Xiaofeng Dou, Peiyu Huang, Jiong Zhou
Show summaryHide summary
BACKGROUND: Anti–amyloid-β (Aβ) therapies can slow cognitive decline and reduce cerebral amyloid burden in Alzheimer’s disease (AD). Neuropsychiatric symptoms (NPS) are highly prevalent across the disease course and substantially contribute to disability and caregiver burden. However, whether Aβ clearance translates into improvements in NPS remains unclear.
METHODS: We enrolled 144 individuals with AD-related mild cognitive impairment or AD dementia who received intravenous lecanemab infusions. Standardized clinical rating scales, including the Neuropsychiatric Inventory, and amyloid PET were assessed at baseline (V0), 6 months (V1), and 12 months (V2). Longitudinal changes in clinical function and amyloid burden were analyzed.
RESULTS: Lecanemab treatment was associated with robust reductions in amyloid PET biomarkers and significant short-term reductions in NPS scores in patients who completed follow-up. Longitudinal analyses showed that reductions in total NPI scores were significantly associated with amyloid-β clearance in the insular cortex. Reductions in the hyperactivity subsyndrome were associated with amyloid reduction across a broader network, including the frontal and temporal lobes, striatum, and insular cortex.
CONCLUSIONS: In this real-world cohort, lecanemab was associated with short-term reductions in NPS. Changes in NPS severity were linked to regional amyloid-β clearance.
CITATION:
Yaping Yan ; Daoyan Hu ; Linlin Kong ; Kaicheng Li ; Jun Su ; Yingzhe Wu ; Hongwei Zhan ; Hong Zhang ; Yidan Sun ; Xiaofeng Dou ; Peiyu Huang ; Jiong Zhou (2025): Reductions in neuropsychiatric symptoms after lecanemab treatment and their associations with imaging markers of β-amyloid clearance. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100600
ASSOCIATION BETWEEN OBSTRUCTIVE SLEEP APNEA SEVERITY AND GLYMPHATIC-RELATED DTI-ALPS ALTERATIONS IN NEWLY DIAGNOSED, DRUG-NAÏVE ALZHEIMER’S DISEASE
Wenxue Zheng, Yao Zhou, Yurui Xia, Yiqing Wang
Show summaryHide summary
BACKGROUND: Obstructive sleep apnea (OSA) is highly prevalent in Alzheimer's disease (AD) patients and is associated with cognitive decline. However, the mechanisms linking OSA to Alzheimer’s pathophysiology, especially regarding glymphatic function, remain unclear. This study investigated the relationship between OSA severity and glymphatic-related diffusion abnormalities, as assessed by the DTI-ALPS index, in newly diagnosed, drug-naïve AD patients.
METHODS: A total of 162 newly diagnosed, drug-naïve AD patients and 98 healthy controls were enrolled. Polysomnography (PSG) was used to assess OSA severity and sleep parameters, while diffusion tensor imaging along the perivascular space (DTI-ALPS) was employed to measure glymphatic function. Correlation analyses, multivariable regression models with interaction terms, and sensitivity analyses were performed to explore the relationship between OSA and glymphatic dysfunction, and whether this relationship was specific to AD.
RESULTS: In AD patients, greater OSA severity was associated with lower ALPS-index values, including AHI (rho = −0.38, P < 0.001) and ODI (rho = −0.35, P < 0.001), whereas these associations were not observed in healthy controls. Lower ALPS-index values were also associated with more fragmented sleep, including higher N1 proportion and arousal index, and with reduced REM sleep. Clinically, the ALPS-index was positively correlated with better cognitive performance on MMSE (rho = 0.28, P = 0.001) and MoCA (rho = 0.31, P < 0.001), and negatively correlated with greater cognitive impairment on ADAS-Cog (rho = −0.34, P < 0.001).
CONCLUSION: Glymphatic dysfunction is related to OSA severity in de novo AD but not in Healthy controls. The study demonstrated that OSA may contribute to neurodegeneration via glymphatic impairment in AD.
CITATION:
Wenxue Zheng ; Yao Zhou ; Yurui Xia ; Yiqing Wang (2025): Association between obstructive sleep apnea severity and glymphatic-related DTI-ALPS alterations in newly diagnosed, Drug-Naïve Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100597
HYPERTENSION ACTS TOGETHER WITH AΒ PATHOLOGY IN LATE-LIFE TO PROMOTE MEMORY LOSS
Lucas U Da Ros, João Pedro Ferrari-Souza, Marco Antônio de Bastiani, Lucas A. Hauschild, Bruna Bellaver, Pamela C.L. Ferreira, Douglas Teixeira Leffa, Guilherme Povala, Firoza Z. Lussier, Mira Chamoun, Gleb Bezgin, Andrea L. Benedet, Nesrine Rahmouni, Arthur C. Macedo, Kaj Blennow, Nicholas Ashton, Henrik Zetterberg, Wyllians Vendramini Borelli, Diogo O. Souza, Tharick A. Pascoal, Pedro Rosa-Neto, Eduardo R. Zimmer, Alzheimer’s Disease Neuroimaging Initiative
Show summaryHide summary
Midlife hypertension (HTN) contributes to cognitive decline in Alzheimer's disease (AD). However, the exact effect of late-life HTN on the AD pathology and on cognitive decline is still controversial. Here, we aimed to assess the impact of HTN and AD pathology in cognitively unimpaired (CU) individuals over 65 years of age on longitudinal cognitive decline. We evaluated 637 CU individuals from two independent cohorts (475 CU individuals from the ADNI cohort; and 162 CU individuals from the TRIAD cohort), with a follow-up of up to 6 years. Linear mixed-effects models showed that HTN and Aβ acted together to promote longitudinal cognitive decline, especially memory loss, in a synergistic way, with a dose-dependent association of blood pressure and Aβ pathology. Hence, HTN in late-life confers additional risk for cognitive decline, particularly for memory loss, in CU individuals at risk of developing dementia due to AD and is a potential modifiable risk factor even at older age.
CITATION:
Lucas U Da Ros ; João Pedro Ferrari-Souza ; Marco Antônio de Bastiani ; Lucas A. Hauschild ; Bruna Bellaver ; Pamela C.L. Ferreira ; Douglas Teixeira Leffa ; Guilherme Povala ; Firoza Z. Lussier ; Mira Chamoun ; Gleb Bezgin ; Andrea L. Benedet ; Nesrine Rahmouni ; Arthur C. Macedo ; Kaj Blennow ; Nicholas Ashton ; Henrik Zetterberg ; Wyllians Vendramini Borelli ; Diogo O. Souza ; Tharick A. Pascoal ; Pedro Rosa-Neto ; Eduardo R. Zimmer ; for theAlzheimer’s Disease Neuroimaging Initiative (): Hypertension acts together with Aβ pathology in late-life to promote memory loss. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100579
EFFECT OF ACCELEROMETER-MEASURED PHYSICAL ACTIVITY ON THE ASSOCIATION BETWEEN ATRIAL FIBRILLATION AND RISK OF DEMENTIA
Le Li, Mengtong Xu, Lingmin Wu, Zhicheng Hu, Limin Liu, Likun Zhou, Minghao Zhao, Yulong Xiong, Zhenhao Zhang, Lihui Zheng, Ligang Ding, Yan Yao
Show summaryHide summary
BACKGROUND: Atrial fibrillation (AF) independently increases dementia risk, but whether accelerometer-measured physical activity (PA) modifies this association remains unquantified, particularly against self-reported PA limitations.
METHODS: Prospective analysis of 91,795 UK Biobank participants with valid accelerometer data (median age 57, 42.9 % male; 2800 with baseline AF). We categorized whether measured activity met the standard recommendation [moderate-to-vigorous physical activity (MVPA) >_150 min/week]. Questionnaire-derived MVPA data from 353,643 UK Biobank participants (median age 57, male: 46.7 %) between 2006 and 2010 were used for validation. The primary outcome was the diagnosis of incident all-cause dementia. We also assessed correlation between accelerometer-derived and self-reported activity.
RESULTS: Over 7.6-year median follow-up, AF was significantly associated with a higher dementia risk [Adjusted hazard ratio (aHR): 1.76, 95 % confidential interval (CI): 1.51–2.05]. Guideline-adherent PA was associated with a lower AF-related dementia risk to non-significance (aHR: 1.36, 95 %CI: 0.96–1.91). Moreover, PA may be associated with higher protection effect on dementia risk in AF patients (aHR: 0.55, 95 % CI: 0.33–0.92) than in non-AF (aHR: 0.81, 95 % CI: 0.69–0.96), although without statistical difference (Pinteraction = 0.213). Correlation between accelerometer-derived and selfreported MVPA was weak (Spearman r = 0.155, 95 % CI: 0.148–0.162). Self-reported activity was not associated with a decreased risk of dementia in both AF and non-AF participants.
CONCLUSION: Higher accelerometer-measured PA is associated with lower AF-associated dementia risk. Future prospective studies with extended follow-up and serial activity monitoring are needed to confirm these findings.
CITATION:
Le Li ; Mengtong Xu ; Lingmin Wu ; Zhicheng Hu ; Limin Liu ; Likun Zhou ; Minghao Zhao ; Yulong Xiong ; Zhenhao Zhang ; Lihui Zheng ; Ligang Ding ; Yan Yao (2025): Effect of accelerometer-measured physical activity on the association between atrial fibrillation and risk of dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100603
LETTER TO THE EDITOR : BEYOND RECOGNITION: REFINING THE ASSESSMENT OF PUBLIC KNOWLEDGE AND RISK PERCEPTION IN DEMENTIA PREVENTION
Zhiyan Xie, Jun Su, Tao Liao
Show summaryHide summary
CITATION:
Zhiyan Xie ; Jun Su ; Tao Liao (2025): Letter to the Editor: Beyond recognition: Refining the assessment of public knowledge and risk perception in dementia prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100602
CLINICAL AND BIOLOGICAL RELEVANCE OF OBJECTIVELY-DEFINED SUBTLE COGNITIVE DECLINE IN ALZHEIMER’S DISEASE: A NARRATIVE REVIEW OF NEUROIMAGING, BIOMARKER, AND CLINICAL PROGRESSION STUDIES
Amanda I. Gonzalez, Jairo E. Martinez, Averi Giudicessi, Meredith Rowe, Vivian Ku, Catarina Tristão-Pereira, Bing He, Vincent Malotaux, Yakeel T. Quiroz
Show summaryHide summary
Preclinical Alzheimer’s Disease stages represent possible targets for disease-modifying intervention as well as opportunity for early identification of risk for future decline. Recent research has explored the use of objectively-defined subtle cognitive decline (Obj-SCD), an emerging classification that may identify individuals at risk for neurodegeneration before the onset of mild cognitive impairment (MCI). The Edmonds/Thomas actuarial Obj‐SCD criteria (> 1 SD below expectations, single cognitive test impaired per domain) aims to capture those who exhibit minimal cognitive difficulties that do not meet a MCI or dementia diagnosis. Given the novelty of the Obj-SCD classification, this narrative review provides an overview of neuroimaging, biomarker, and clinical progression studies to evaluate its biological and clinical significance. Using fluid-based biomarkers, neuroimaging, and longitudinal designs, studies have indicated that the Obj-SCD classification has the potential to capture AD-related pathological changes detectable before the clinical onset of MCI. In particular, recent studies indicate a unique pathological profile of Obj-SCD, differentiating it from the cognitively unimpaired and MCI stages. Studies comparing Obj-SCD and subjective cognitive complaints show that the Obj-SCD criteria may be more closely associated to early AD pathology. While the existing literature is limited, findings uphold Obj-SCD as a sensitive classification able to identify individuals at risk for future cognitive impairment. Studies on Obj-SCD indicate utility in research settings, although it faces challenges regarding its clinical implementation and effectiveness.
CITATION:
Amanda I. Gonzalez ; Jairo E. Martinez ; Averi Giudicessi ; Meredith Rowe ; Vivian Ku ; Catarina Tristão-Pereira ; Bing He ; Vincent Malotaux ; Yakeel T. Quiroz (2025): Clinical and biological relevance of objectively-defined subtle cognitive decline in Alzheimer’s disease: a narrative review of neuroimaging, biomarker, and clinical progression studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100604
BIOMARKERS IN PRECLINICAL AND EARLY ALZHEIMER’S DISEASE IN CHINA: A SCOPING REVIEW
Guoping Peng, Yan Yang, Ying Wang, Sagar Anil Chandekar, Jintai Yu
Show summaryHide summary
This scoping review synthesizes evidence on fluid and neuroimaging biomarkers for preclinical and early Alzheimer’s disease (AD)—including mild cognitive impairment (MCI) and mild AD dementia—in Chinese populations, where a comprehensive overview has been lacking despite AD's increasing biomarker-based definition. We systematically searched four English databases (PubMed, EMBASE, Cochrane, and Web of Science) and three Chinese databases (CNKI, Wanfang, and CQVIP) for studies (2013–2023) reporting diagnostic accuracy of these biomarkers in Chinese preclinical and early AD (eAD) cohorts for clinical use. Due to rapid advancements in biomarker research in China, a supplementary search was conducted in the four English databases for studies published between 2024 and April 30, 2025. Of the 366 included studies investigating fluid or neuroimaging biomarkers in AD, 48 specifically evaluated biomarker performance in biomarker‑confirmed AD populations. Plasma p-tau217 showed strong performance for diagnosing MCI due to AD, and plasma p-tau217, p-tau181/Aβ42, and p-tau217/Aβ42 effectively classified amyloid-β (Aβ) pathology. Multimodal combinations and MRI-based biomarkers also performed well, though evidence is limited. In China, biomarker diagnosis of MCI due to AD is advancing rapidly, while approaches for preclinical AD, machine learning, and multi-protein panels remain in early development.
CITATION:
Guoping Peng ; Yan Yang ; Ying Wang ; Sagar Anil Chandekar ; Jintai Yu (2025): Biomarkers in preclinical and early Alzheimer’s disease in China: a scoping review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100599
NEUROPSYCHIATRIC SYMPTOMS AND DEMENTIA DEVELOPMENT: A 15-YEAR POPULATION-BASED STUDY
Francesca Remelli, Giulia Grande, Serhiy Dekhtyar, Erika J Laukka, Caterina Trevisan, Stefano Volpato, Laura Fratiglioni, Federico Triolo
Show summaryHide summary
BACKGROUND: Mild Behavioral Impairment (MBI) has been proposed to detect neuropsychiatric symptoms (NPS) associated with dementia development, but evidence from population-based settings is limited.
OBJECTIVES: To (i) investigate the association between NPS in late life and the onset of dementia over 15 years in community-dwelling older adults, and (ii) test the interplay of NPS and Cognitive Impairment, No Dementia (CIND) in dementia development.
METHODS: 2597 dementia-free individuals aged 60+ from a longitudinal population-based cohort underwent cognitive assessments over 15 years. Thirty clinically-assessed NPS were mapped into five domains and, within each domain, a z-score was computed from the sum of the NPS’s points. MBI was identified when the z-score was above 1.5 standard deviations (SDs) in at least one of 5 neuropsychiatric domains. Based on a cognitive battery, CIND was defined as scoring ≥1.5 SDs below age-specific means in at least one cognitive domain. Dementia was diagnosed by DSM-IV criteria following standardized procedures.
RESULTS: MBI, present in 16.1% of the sample, was associated with a higher hazard of incident dementia over 15 years (multi-adjusted hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.31–2.17). Decreased motivation and social inappropriateness were the domains associated with incident dementia (HR 2.23, 95%CI 1.59–3.14 and HR 3.29, 95%CI 1.83–5.94, respectively). Compared to those with neither, individuals with either MBI (HR 1.37, 95%CI 1.00–1.90) or CIND (HR 2.22, 95%CI 1.73–2.84) had increased dementia incidence, especially when co-occurring (HR 4.41, 95%CI 3.04–6.39).
CONCLUSIONS: Late life NPS, especially with co-occurring cognitive impairment, was associated with a higher dementia incidence.
CITATION:
Francesca Remelli ; Giulia Grande ; Serhiy Dekhtyar ; Erika J Laukka ; Caterina Trevisan ; Stefano Volpato ; Laura Fratiglioni ; Federico Triolo (2025): Neuropsychiatric symptoms and dementia development: a 15-year population-based study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100596
CLASS-LEVEL AGGREGATION OBSCURES CLINICALLY RELEVANT HETEROGENEITY IN ANTI-AMYLOID ANTIBODY TRIALS: COMMENTS ON A COCHRANE REVIEW BY INDIVIDUAL MEMBERS OF THE EADC
Kristian Steen Frederiksen, Mercè Boada, Lutz Frölich, Milica Kramberger, Nikolaos Scarmeas, Everard Vijverberg, Pieter Jelle Visser, Gunhild Waldemar, Eric Westman, Henrik Zetterberg, Sebastiaan Engelborghs, Frank Jessen
Show summaryHide summary
CITATION:
Kristian Steen Frederiksen ; Mercè Boada ; Lutz Frölich ; Milica Kramberger ; Nikolaos Scarmeas ; Everard Vijverberg ; Pieter Jelle Visser ; Gunhild Waldemar ; Eric Westman ; Henrik Zetterberg ; Sebastiaan Engelborghs ; Frank Jessen (2025): Class-level aggregation obscures clinically relevant heterogeneity in anti-amyloid antibody trials: comments on a Cochrane review by individual members of the EADC. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100598
INTERACTION OF DIET AND PHYSICAL ACTIVITY ON DEMENTIA RISK: THE ROTTERDAM STUDY
Muhammed Lamin Sambou, M. Arfan Ikram, M. Kamran Ikram, Jeremy A. Labrecque, Frank J. Wolters
Show summaryHide summary
BACKGROUND: Diet and physical activity have been reported as independent risk factors for dementia, but few published studies have investigated the interactive effects of the two on dementia risk. Understanding their synergism could help shape more effective prevention strategies. Therefore, we assessed the potential interactions between MIND diet adherence and physical activity on the long-term risk of incident dementia in the population-based Rotterdam Study.
METHODS: Between 2009–2013, 5016 participants of the population-based Rotterdam Study were recruited (mean age 69.76 years, 57.9% women). All participants filled in questionnaires regarding their adherence to the MIND diet and time spent on moderate to vigorous physical activity (Metabolic Equivalent of Task [MET] hours per week). Participants were subsequently followed for incident dementia until January 1, 2021. We applied multivariable Cox regression models to assess interaction on both additive and multiplicative scales.
RESULTS: Median values were 7.5 for the MIND diet score and 28.0 for MET hours per week. Of all 5016 participants, 2718 (54.2%) adhered to a high MIND diet score (≥7.5), and 2513 (50.1%) reached at least 28.0 MET hours per week. During a mean follow-up of 6.6 years, 365 participants (7.8%) developed dementia. Both higher physical activity and higher MIND-diet score were independently associated with a lower risk of dementia, but there was no significant interaction on the additive scale (RERI [95%CI]=-0.42 [-1.26 to 0.12]), nor on the multiplicative scale (HRinteraction=0.71 [0.46–1.09]). Sex-stratified analysis suggested a negative interaction between exposures in women, but not in men.
CONCLUSION: Better adherence to the MIND-diet and higher levels of physical activity were each associated with a reduced risk of dementia, but overall there was no indication that their joint effects were greater than the product or sum of their individual parts. Potential sex differences warrant further exploration in different populations.
CITATION:
Muhammed Lamin Sambou ; M. Arfan Ikram ; M. Kamran Ikram ; Jeremy A. Labrecque ; Frank J. Wolters (2025): Interaction of diet and physical activity on dementia risk: the Rotterdam study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100594
EPIGENETIC AGING AND BLOOD BASED NEURODEGENERATION MARKERS IN LASI-DAD
Jung Ki Kim, Thalida E. Arpawong, Bharat Thyagarajan, Jennifer A. Smith, Sithara Vivek, Scott Ratliff, Sharmistha Dey, Jinkook Lee, Eileen M. Crimmins
Show summaryHide summary
DNA methylation (DNAm)-based epigenetic clocks are emerging biomarkers of biological aging and have been linked to cognitive decline and dementia, but their relationship with blood-based neurodegenerative biomarkers remains understudied in low- and middle-income countries (LMIC). Using the Longitudinal Aging Study in India-Diagnostic Assessment of Dementia (LASI-DAD), we examined whether epigenetic aging was associated with levels and changes in neurodegenerative biomarkers among adults aged ≥60 years. Seven epigenetic clocks were derived from DNAm data and related to plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), phosphorylated tau 181 (pTau181), total tau, Amyloid-β (Aβ)42, Aβ40 and Aβ42/Aβ40 measured at two time points. Baseline accelerated epigenetic aging was associated with higher levels of neurodegenerative biomarkers, including pTau181, GFAP, and NfL, with more consistent associations with increases in GFAP and NfL for morbidity- and mortality-trained clocks. These findings support the utility of epigenetic clocks as scalable tools for identifying risk of neurodegeneration in LMIC settings.
CITATION:
Jung Ki Kim ; Thalida E. Arpawong ; Bharat Thyagarajan ; Jennifer A. Smith ; Sithara Vivek ; Scott Ratliff ; Sharmistha Dey ; Jinkook Lee ; Eileen M. Crimmins (2025): Epigenetic aging and blood based neurodegeneration markers in LASI-DAD. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100595
SLEEP COMPLAINTS AND GENETIC RISK OF ALZHEIMER’S DISEASE IN OLDER WOMEN: ASSOCIATIONS WITH MEMORY AND TAU DEPOSITION
Kitty K Lui, Xin Wang, Melanie A Dratva, Ella T. Lifset, Jordan Stiver, Nadine C. Heyworth, Qian Shen, Michael Thomas, Pamela N. DeYoung, Atul Malhotra, Erin E. Sundermann, Sarah J. Banks
Show summaryHide summary
BACKGROUND: Emerging evidence point to a bidirectional relationship between sleep disturbances and Alzheimer’s disease (AD). Poor sleep may be an overlooked risk factor for older women, who are disproportionately affected by AD and report worse subjective sleep quality than men. High genetic AD risk—characterized by the polygenic hazard score (PHS), including apolipoprotein (APOE) ε4 carriership—may further compound the effects of disrupted sleep on AD, particularly for older women.
OBJECTIVE: This study examined the moderating effect of genetic AD risk on subjective sleep as it related to memory and tau burden in a sample of older women.
PARTICIPANTS: The sample consisted of older women (≥65 years old) from the Women Inflammation Tau Study.
MEASUREMENT: Participants completed the Pittsburgh Sleep Quality Index (PSQI), Rey Auditory Learning Test, and Brief Visuospatial Memory Test-Revised. They also underwent [18]F-MK6240 positron emission tomography. Tau burden was calculated in composite regions across Braak stages. Genetic risk groups were characterized by PHS stratified at the 75th percentile. PSQI global score × PHS group interactions on memory composite scores (N = 69) and tau burden (N = 63) were examined.
RESULTS: PSQI global score × PHS group interactions were observed on visual memory and pathological tau in Braak regions III/IV (ps<0.10). Poorer subjective sleep was associated with worse visual memory and greater limbic tau deposition only among higher genetic risk women (ps<0.04). No significant associations were observed for verbal memory or tau in Braak regions I/II or V/VI.
CONCLUSION: Older women with elevated genetic AD risk and subjective sleep difficulties may be at greater risk for visual memory deficits and tau burden in regions affected in early AD. This suggests that sleep complaints may represent a promising AD risk factor. Improving sleep may be a potential intervention target for AD mitigation and prevention, particularly for older women.
CITATION:
Kitty K Lui ; Xin Wang ; Melanie A Dratva ; Ella T. Lifset ; Jordan Stiver ; Nadine C. Heyworth ; Qian Shen ; Michael Thomas ; Pamela N. DeYoung ; Atul Malhotra ; Erin E. Sundermann ; Sarah J. Banks (2025): Sleep complaints and genetic risk of Alzheimer’s disease in older women: associations with memory and tau deposition. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2025.8
LETTER TO THE EDITORE: CLARITY AD OPEN-LABEL EXTENSION DATA DO NOT ROBUSTLY CONFIRM DISEASE COURSE MODIFICATION BY LECANEMAB IN APOE4 HETEROZYGOTES AND NON-CARRIERS
Lutz Froelich
Show summaryHide summary
CITATION:
Lutz Froelich (2025): Letter to the editor: Clarity AD open-label extension data do not robustly confirm disease course modification by lecanemab in ApoE4 heterozygotes and non-carriers. # TJPAD-D-26-00165. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100588
RNA-BASED THERAPEUTICS FOR ALZHEIMER’S DISEASE AND RELATED TAUOPATHIES: CHALLENGES AND OPPORTUNITIES
Binita Rajbanshi, Ilaria Brentari, Michela Alessandra Denti, Jeffrey L. Cummings, Anuj Guruacharya
Show summaryHide summary
Tauopathies are neurodegenerative diseases characterized by pathological tau protein accumulation. Though therapies involving monoclonal antibodies and small-molecule inhibitors have progressed, they have so far failed in multiple clinical trials, underscoring the need for innovative molecular approaches. RNA-based therapies offer an alternative disease-modifying approach by being able to target tau at its molecular origin. Diverse modalities, such as mRNA, ASO, RNAi, and SSO, offer distinct promises. Though their challenges are equally diverse, they also share common problems. This review examines the nascent field of RNA therapeutics for tauopathies, outlining emerging modalities, translational barriers, molecular targets, clinical trials, and patent trends.
CITATION:
Binita Rajbanshi ; Ilaria Brentari ; Michela Alessandra Denti ; Jeffrey L. Cummings ; Anuj Guruacharya (2025): RNA-based therapeutics for Alzheimer’s disease and related tauopathies: challenges and opportunities. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100585
TOP FIVE ALZHEIMER DISEASE TRIAL ELIGIBILITY CRITERIA FAVOR MEN COMPARED TO WOMEN IN A CLINIC-BASED COHORT
Lieza G. Exalto, Siti S. Syaziyah, Xiaotian T Fang, Niels D. Prins, Sietske A.M. Sikkes, Wiesje M. van der Flier, Everard G.B. Vijverberg, Yvonne M.F. Lim
Show summaryHide summary
BACKGROUND: Less women participate in Alzheimer Disease (AD) trials compared to their estimated representation in the global dementia population.
OBJECTIVES: We aimed to apply five most commonly used eligibility criteria to a real-world memory clinic population to compare male and female eligibility according to these criteria.
DESIGN: Observational.
SETTING: Memory clinic setting.
PARTICIPANTS: Consecutive patients (2000–2024) from Amsterdam Dementia Cohort with a diagnosis of mild cognitive impairment (MCI) or AD (n = 3835).
MEASUREMENTS: Free-text eligibility criteria of n = 608 phase II and III AD drug trials were downloaded from ClinicalTrials.gov (March 28, 2025). A machine-learning model was trained and validated to extract all eligibility criteria. Next the criteria were applied on observational real world data from on memory clinic diagnostic work-up.
RESULTS: Top 5 most common AD clinical trial eligibility criteria were 1) no other central nervous system disorder related to cognitive impairment (84%), 2) participation of a caregiver (72%), 3) MMSE (66%, range 20–30), 4) no comorbidities, specifically vascular and mental health (62%), 5) no contra-indications for study procedures such as lumbar puncture, MRI and PET (59%). Applying the abovementioned criteria results in 33% of men and 23% of women remaining eligible (p<.001). Main reason for non-eligibility is caretaker absence (applicable for 20% of men and 38% of women) and low MMSE (32% of man and 54% of women).
CONCLISION: Based on five commonly used eligibility criteria of AD clinical trials, women in our clinic-based cohort are less eligible for participation in AD drug trials than men. This discrepancy was mainly attributed to lack of caregiver presence and lower MMSE at presentation. These results provide clues for trial design to facilitate more equal inclusion of women.
CITATION:
Lieza G. Exalto ; Siti S. Syaziyah ; Xiaotian T Fang ; Niels D. Prins ; Sietske A.M. Sikkes ; Wiesje M. van der Flier ; Everard G.B. Vijverberg ; Yvonne M.F. Lim (2025): Top five Alzheimer Disease trial eligibility criteria favor men compared to women in a clinic-based cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100580
VIRTUAL REALITY-BASED TRAINING IN PATIENTS WITH ALZHEIMER\'S DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS
Junjie Wang, Can Wu, Kedong Zhu, Xiaoshan Qi, Guiqin Chen
Show summaryHide summary
BACKGROUND AND OBJECTIVES: Prior meta-analyses have suggested that training utilizing virtual reality (VR) serves as a secure and effective intervention for elderly individuals experiencing mild cognitive impairment (MCI). Nevertheless, the effectiveness of such interventions appears to differ among various populations and cognitive domains. Furthermore, there remains a significant gap in understanding the effectiveness of VR-based training, specifically among individuals diagnosed with Alzheimer's disease (AD).
METHODS: The researchers conducted a comprehensive search of databases, including Web of Science, PubMed, Cochrane Library, and EMBASE up until July 1, 2025, focusing on randomized controlled trials that investigated VR-based training in patients diagnosed with AD. The outcomes measured were categorized and analyzed separately, encompassing overall cognitive performance, distinct cognitive domains, psychosocial function, physical capabilities, and the execution of daily living activities within the context of AD trials.
RESULTS: Of the 265 publications identified, 11 (4.15%) randomized controlled trials (RCTs) eventually met all eligibility criteria. Those who received VR-based training showed significantly better global cognitive function [SMD (95%CI) = 0.44 (0.21–0.68)] and Short-term memory [SMD (95%CI) = 0.62 (0.25–0.99)] than the controls. However, no significant improvements were observed in areas such as executive function, spatial memory, activities of daily living, quality of life, balance and coordination, fear of falling, risk of falls, and depression levels.
CONCLUSION: VR-based interventions demonstrated beneficial effects on global cognitive function and short-term memory in AD populations. Due to the small sample size, the current research on evidence for efficacy in people with AD is weak and limited in many indicators.
CITATION:
Junjie Wang ; Can Wu ; Kedong Zhu ; Xiaoshan Qi ; Guiqin Chen (2025): Virtual reality-based training in patients with alzheimer's disease: A systematic review and meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100590
ADAPTING THE SPANISH HEALTHCARE SYSTEM FOR DISEASE-MODIFYING TREATMENTS IN EARLY-STAGE ALZHEIMER’S DISEASE
R. Sánchez Valle, A. Lleó Bisa, A. Villarejo Galende, E. Cuartero Rodríguez, J. Escudero-Torrella, N. Bargallo Alabart
Show summaryHide summary
BACKGROUND: The emergence of disease-modifying therapies targeting amyloid pathology represents a major paradigm shift in the management of Alzheimer disease (AD). However, their implementation poses substantial organizational, infrastructural, and clinical challenges for health systems.
OBJECTIVES: To identify the key challenges and establish priority recommendations for the effective incorporation of amyloid-targeting therapies into the Spanish National Health System.
DESIGN, SETTING, AND PARTICIPANTS: This multiphase consensus study was conducted within the Spanish National Health System between September 2024 and July 2025. The study comprised a narrative literature review, qualitative research, regional workshops, and a modified RAND/UCLA Delphi process. A total of 56 experts participated, including a scientific committee of 6 Alzheimer disease specialists and an expert panel of 50 multidisciplinary professionals involved in AD care.
MEASUREMENTS: Identification of key challenges across the AD care pathway; development, evaluation, and prioritization of consensus-based recommendations; and estimation of patient demand, including projected increases in day hospital activity and magnetic resonance imaging utilization.
RESULTS: Ten key challenge areas were identified, encompassing early detection and referral, diagnostic confirmation, assessment of patient eligibility, treatment administration in day hospitals, monitoring of amyloid-related imaging abnormalities, evaluation of treatment effectiveness, infrastructure and capacity, professional training, patient information and support, and health care planning. Of the 43 recommendations assessed, 38 were rated as appropriate and necessary, with 14 prioritized for immediate implementation. Demand estimation models indicated that 11 to 26 patients per 100,000 inhabitants could be treated under current care patterns, increasing to 17 to 115 per 100,000 inhabitants under alternative eligibility scenarios.
CONCLUSIONS: This consensus defines the clinical, organizational, and infrastructural requirements necessary to integrate amyloid-targeting therapies into routine care within the Spanish National Health System. The prioritized recommendations define immediate actions to address the challenges identified and may serve as a reference for other health systems facing similar implementation processes.
CITATION:
R. Sánchez Valle ; A. Lleó Bisa ; A. Villarejo Galende ; E. Cuartero Rodríguez ; J. Escudero-Torrella ; N. Bargallo Alabart (2025): Adapting the spanish healthcare system for disease-modifying treatments in early-stage alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100586
PHENOTYPING OF MILD BEHAVIORAL IMPAIRMENT DOMAINS IN MULTI-REGIONAL DEMENTIA-FREE OLDER ADULTS OF CHINESE ETHNICITY: IMPULSE DYSCONTROL AS THE LEADING DOMAIN
Yingqi Liao, Yaping Zhang, Haoran Zhang, Yan Li, Dylan X. Guan, Yifan Yan, Yuek Ling Chai, Mitchell K.P. Lai, Shifu Xiao, Christopher L.H. Chen, Xin Xu
Show summaryHide summary
BACKGROUND: Mild behavioral impairment (MBI) is an early neurobehavioral marker of dementia, yet MBI domain patterns remain underexplored among populations of Chinese ethnicity. This study aimed to characterize MBI domain phenotypes by examining the prevalence of MBI domains and identifying the leading domain across multi-regional cohorts of dementia-free older adults of Chinese ethnicity.
METHODS: Data from three previously unpublished datasets (Hangzhou community cohort, China Longitudinal Aging Study and Singapore memory clinic cohort) and three published studies were integrated to estimate the MBI domain prevalence, measured by the Neuropsychiatric Inventory (NPI) and/or MBI-Checklist (MBI-C), through a random-effects meta-analysis. Within the Hangzhou cohort, cross-instrument consistency was evaluated. Exploratory analyses were performed in the Singapore cohort on associations between MBI domains and incident dementia.
RESULTS: Among 1817 participants, impulse dyscontrol was the most prevalent MBI domain, followed by affective dysregulation and decreased motivation, consistently across instruments and cognitive status. In the exploratory longitudinal analyses, impulse dyscontrol was associated with a greater likelihood of incident dementia (HR = 5.05, 95%CI = 2.92 – 8.73).
CONCLUSIONS: Impulse dyscontrol was the leading MBI domain among older adults of Chinese ethnicity, with potential clinical relevance for early identification and dementia risk stratification.
CITATION:
Yingqi Liao ; Yaping Zhang ; Haoran Zhang ; Yan Li ; Dylan X. Guan ; Yifan Yan ; Yuek Ling Chai ; Mitchell K.P. Lai ; Shifu Xiao ; Christopher L.H. Chen ; Xin Xu (2025): Phenotyping of mild behavioral impairment domains in multi-regional dementia-free older adults of Chinese ethnicity: impulse dyscontrol as the leading domain. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100589
LETTER TO THE EDITOR: CLARITY AD OPEN-LABEL EXTENSION DATA DO NOT ROBUSTLY CONFIRM DISEASE COURSE MODIFICATION BY LECANEMAB IN APOE4 HETEROZYGOTES AND NON-CARRIERS
Jemma Hazan, Kathy Y. Liu, Robert Howard
Show summaryHide summary
CITATION:
Jemma Hazan ; Kathy Y. Liu ; Robert Howard (2025): Letter to the Editor: Clarity AD open-label extension data do not robustly confirm disease course modification by lecanemab in ApoE4 heterozygotes and non-carriers. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100587
INCOME, DIET, AND COGNITIVE FUNCTION: OBSERVATIONAL ANALYSES AND CANDIDATE METABOLOMIC PATHWAYS IDENTIFIED BY MENDELIAN RANDOMIZATION
Xingguang Zhao, Weijian Wu, Qiaoxuan Zhang, Mengqian Ouyang, Haoyu Luo, Qun Yu, Yingren Mai, Zhiyu Cao, Shaoqing Yang, Mingsong Xu, Jun Liu, Wang Liao
Show summaryHide summary
BACKGROUND: Household income has been shown to have impact on cognitive function, with dietary patterns and gut microbiota–related metabolic pathways potentially acting as mediating pathways. Our study integrates observational analyses and Mendelian randomization (MR) to explore these associations.
METHODS: The observational analysis included 13,457 participants from the UK Biobank who experienced cognitive transitions. A multistate Markov model was applied to assess the effect of income level on cognitive trajectory, while mediation analysis and quantile regression were performed using baseline data. We applied a two-sample, two-step MR approach utilizing genetic instruments from the IEU Open genome-wide association studies (GWAS) project to determine the causal effects of income on cognition, and further estimate the mediating roles of dietary patterns and 1400 gut metabolites linking income with cognitive performance.
RESULTS: Over a median follow-up of 8.96 years, a total of 14,040 cognitive transitions were recorded (7429 deterioration events and 6801 improvements), with higher income associated with a lower risk of cognitive deterioration. MR analyses confirmed a causal relationship between income and cognitive performance (OR: 2.140, 95% CI: 1.923–2.381; P < 0.001). Notably, cheese and coffee intake demonstrated significant mediation effects in both observational and two-way, two-step MR. The protective effect of cheese appeared to be mediated by gut metabolites, particularly via tryptophan/tyrosine and carnitine/ergothioneine.
CONCLUSIONS: Our findings indicate a significant link between income and cognitive performance, cheese and dried fruit may mediate this protective effect through amino acid and carnitine metabolism pathways. Interventions targeting dietary patterns have the potential to prevent cognitive decline attributable to low income.
CITATION:
Xingguang Zhao ; Weijian Wu ; Qiaoxuan Zhang ; Mengqian Ouyang ; Haoyu Luo ; Qun Yu ; Yingren Mai ; Zhiyu Cao ; Shaoqing Yang ; Mingsong Xu ; Jun Liu ; Wang Liao (2025): Income, diet, and cognitive function: observational analyses and candidate metabolomic pathways identified by Mendelian randomization. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100582
TETANUS, DIPHTHERIA AND PERTUSSIS VACCINATION AND RISK FOR INCIDENT DEMENTIA AMONG ADULTS WITH DOWN SYNDROME
Kimberly Schiel, Joanne Salas, Anjani Urban, Daniel F. Hoft, Jeffrey F. Scherrer
Show summaryHide summary
BACKGROUND: Adult vaccination is inversely associated with incident Alzheimer’s Disease and Related Dementias.
OBJECTIVES: We determined if Tetanus, Diphtheria and Pertussis (Tdap) vaccination was linked to incident Alzheimer’s Disease and dementia among adults with Down Syndrome, 50% of whom develop Alzheimer’s Disease by age 60.
DESIGN: This is a retrospective cohort study using TriNetX nationally distributed electronic health records from 2013 to 2024.
SETTING: Historical medical record data.
PARTICIPANTS: 5591 patients with Down Syndrome across the United States. Eligible patients were free of Alzheimer’s Disease and dementia prior to index. Index date could occur 1/1/2015 to 1/1/2020 allowing for 5 to 10 years of possible follow-up time.
MEASUREMENTS: Vaccination was measured using product name and procedure codes and Alzheimer’s Disease and dementias was defined by ICD-10 codes.
RESULTS: The mean age of the cohort was 50.0 (±8.3), 50.1% were female and 72.1% were White. After controlling for confounding, Tdap vaccination vs. remaining without Tdap vaccination was associated with lower Alzheimer’s Disease and dementia risk (HR=0.74; 95%CI:0.57–0.98).
CONCLUSIONS: In a cohort of patients with Down Syndrome, Tdap vaccination was associated with a 26% lower risk for Alzheimer’s Disease and dementia. This is a novel and important finding because existing studies of vaccination and reduced risk for Alzheimer’s Disease and dementia have been among cognitively intact adults. This study reveals benefits of vaccination even among those at high risk for Alzheimer’s Disease and dementia due to Down Syndrome. Future studies are needed to understand the mechanisms underlying this relationship.
CITATION:
Kimberly Schiel ; Joanne Salas ; Anjani Urban ; Daniel F. Hoft ; Jeffrey F. Scherrer (2025): Tetanus, diphtheria and pertussis vaccination and risk for incident dementia among adults with down syndrome. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100583
JPAD Volume 13, N°06 - 2026
EDITORIAL : LIPID-LOWERING REGIMENS IN ALZHEIMER’S DISEASE DEMENTIA: SMALL EFFECTS WITH POTENTIAL LONG-TERM BENEFIT
Tobias Hartmann
J Prev Alz Dis 2026;6(13)
Show summaryHide summary
CITATION:
Tobias Hartmann (2025): Editorial: Lipid-lowering regimens in Alzheimer’s disease dementia: small effects with potential long-term benefit. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100576
HYPOLIPIDEMICS REDUCE THE RATE OF ALZHEIMER\'S DISEASE DEVELOPMENT AND DEMENTIA PROGRESSION: A COHORT STUDY LINKED WITH GENETIC AND NEUROPATHOLOGICAL ANALYSES
Zohi Sternberg, Rebecca E. Podolsky, Jihnhee Yu, Shuangcheng Hua, Stanley Halvorsen, Bernhard J. Schaller
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: High cholesterol contributes to the development and progression of dementia due to both Alzheimer's disease (A.D.) and vascular pathology. However, the effects of lipid-lowering regimen (LLR) on cognitive dysfunction and brain neuropathology are unknown.
OBJECTIVE: To investigate the effect of LLR on the conversion from normal to mild cognitive impairment (MCI), indicated by CDR-SOB of >0–2.5 (MCI), and the progression to dementia, indicated by CDR-SOB =>3 (10-year follow-up) and LLR effect on the rate of survival (15-year follow-up). Participants were stratified by age (≤70 years and >70 years), gender, and the presence of at least one copy of the APOE4 allele. We also analyzed the effect of LLR on brain neuropathology in participants, indicated by Braak staging, hippocampal atrophy, and CSF levels of total Tau. The differential effect of LLR, with or without cerebrovascular disease, lacunar infarct, or cystic infarction in the cognitive network, was analyzed.
METHODS: We have analyzed the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS).
RESULTS: In participants with CDR-SOB of >0–2.5, the use of hypolipidemic agents was associated with a reduced yearly increase in the CDR-SOB scores by 0.0088 (0.0038, 0.0138) unit (P < 0.001). This effect was more pronounced in participants with CDR-SOB =>3 showing a reduced yearly increase in the CDR-SOB scores by 0.1733 (0.1441, 0.2025) unit (P < 0.001) in LLR-users compared to non-users, and an increased rate of survival [HR: 0.822 (0.746, 0.906). P = 0.001]. The pattern persisted when participants were stratified based on age, gender, and the presence of APOE4. LLR had no significant effect on Braak staging scores, hippocampal atrophy, and total CSF Tau level, and was independent of the presence or absence of cerebrovascular disease, lacunar infarct, and cystic infarction in cognitive network.
CONCLUSION: Our results have implications for delaying cognitive dysfunction and halting the progression of dementia, regardless of the etiology being related to AD or vascular pathology.
CITATION:
Zohi Sternberg ; Rebecca E. Podolsky ; Jihnhee Yu ; Shuangcheng Hua ; Stanley Halvorsen ; Bernhard J. Schaller (2025): Hypolipidemics reduce the rate of Alzheimer's disease development and dementia progression: A cohort study linked with genetic and neuropathological analyses. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100555
EDITORIAL : BEYOND AMYLOID POSITIVITY: BIOLOGICAL HETEROGENEITY IN THE REAL-WORLD USE OF LECANEMAB
Michael S. Rafii
J Prev Alz Dis 2026;6(13)
Show summaryHide summary
CITATION:
Michael S. Rafii (2025): Editorial: Beyond amyloid positivity: Biological heterogeneity in the real-world use of lecanemab. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100584
ATNIVS BIOMARKER HETEROGENEITY IN REAL-WORLD PATIENTS RECEIVING LECANEMAB
Masanori Kurihara, Ryoko Ihara, Gen Yoshii, Ryosuke Shimasaki, Keiko Hatano, Taro Bannai, Fumio Suzuki, Kenji Ishibashi, Ko Furuta, Katsuya Satoh, Aya Midori Tokumaru, Kenji Ishii, Atsushi Iwata
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: While amyloid-β (Aβ) biomarker positivity is sufficient before initiating anti-Aβ antibody therapy, recent revised criteria also highlight the importance of other biomarkers (ATNIVS) to understand heterogeneity in AD.
DESIGN, SETTING, AND PARTICIPANTS: We reviewed patients who attended our specialty clinic between December 2023 and October 2024. Some participated in tau PET study (18F-MK6240). MRI was assessed using Fazekas score. Remaining samples were analyzed for plasma neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and CSF α-synuclein seed amplification assay (SAA).
RESULTS: During the period, 200 attended and 147 proceeded to screening. Lecanemab was started in 93 of 108 A+ patients; mean age 74.2 years, 73.1% female. While all tested started on lecanemab were positive on amyloid PET, 21% had only regional positivity with lower Aβ burden (centiloid 31.3 ± 17.5 vs 67.6 ± 20.2) and higher age (79.2 ± 5.1 vs 73.3 ± 8.9). While all tested had CSF Aβ42/40 values below the single cut-off 0.067 in Japan, three (8.6%) had values close to the cutoff (0.059–0.067), all of whom were male. Other biomarkers also widely varied from normal to fully abnormal; CSF pTau181 (40.5–168 pg/mL, cut-off 56.5), tau PET-based Braak stage (0–VI), NfL (10.0–103.3 pg/mL), GFAP (121.9–652.5 pg/mL), Fazekas score (0–3), and positive α-synuclein SAA (25–33%). Some associations were indicated including higher Fazekas scores in amyloid PET regional-positive group and higher plasma NfL in CSF Aβ42/40 0.059–0.067 group.
CONCLUSIONS: We identified substantial heterogeneity in ATNIVS biomarker profiles among patients receiving lecanemab in a real-world setting.
CITATION:
Masanori Kurihara ; Ryoko Ihara ; Gen Yoshii ; Ryosuke Shimasaki ; Keiko Hatano ; Taro Bannai ; Fumio Suzuki ; Kenji Ishibashi ; Ko Furuta ; Katsuya Satoh ; Aya Midori Tokumaru ; Kenji Ishii ; Atsushi Iwata (2025): ATNIVS biomarker heterogeneity in real-world patients receiving lecanemab. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100567
AMYLOID-RELATED IMAGING ABNORMALITIES IN JAPANESE PATIENTS WITH ALZHEIMER’S DISEASE TREATED WITH LECANEMAB: A REAL-WORLD STUDY
Ryosuke Shimasaki, Masanori Kurihara, Taro Bannai, Keiko Hatano, Fumio Suzuki, Aya Midori Tokumaru, Kenji Ishii, Ryoko Ihara, Atsushi Iwata
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Although clinical trials have suggested a lower incidence of adverse events associated with Lecanemab in Asian populations compared to global cohorts, longitudinal real-world data across broader clinical indications are necessary to confirm these findings in routine practice.
OBJECTIVES: This study aimed to provide real-world evidence regarding the safety profile of Lecanemab in Japanese patients in a clinical setting.
DESIGN: A real-world observational study with a follow-up period of up to 18 months.
SETTING: A single center in Japan.
PARTICIPANTS: We included 120 Japanese patients who received Lecanemab between December 2023 and November 2025 and underwent at least one brain MRI before the fifth infusion.
MEASUREMENTS: Safety outcomes included amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation.
RESULTS: The mean age was 74.2 ± 7.9 years, and 89 (74%) were female. The majority of patients (88%) had a baseline CDR global score of 0.5. During follow-up, 81 patients completed the 12-month assessment. ARIA occurred in 24 patients (20%); ARIA-E with or without ARIA-H occurred in 5 patients (4%), and isolated ARIA-H occurred in 19 patients (16%). Crucially, no patients experienced symptomatic ARIA. All patients with ARIA-E who had available APOE data were ε4 carriers. Patients with ARIA had significantly lower baseline MMSE scores (p = 0.04), alongside non-significant trends toward higher plasma GFAP levels (p = 0.11) and higher deep white matter Fazekas scores (p = 0.05). IRRs occurred in 34 patients (28%), all of which were mild. Treatment was discontinued in 19 patients (16%), mainly due to disease progression (n = 8).
CONCLUSION: In this Japanese AD cohort, Lecanemab demonstrated a manageable safety profile in a real-world setting. In exploratory analyses, potential trends toward a higher frequency of ARIA were observed in patients with lower MMSE scores, higher plasma GFAP levels, and higher Fazekas scores, underscoring the importance of individualized risk assessment prior to therapy.
CITATION:
Ryosuke Shimasaki ; Masanori Kurihara ; Taro Bannai ; Keiko Hatano ; Fumio Suzuki ; Aya Midori Tokumaru ; Kenji Ishii ; Ryoko Ihara ; Atsushi Iwata (2025): Amyloid-related imaging abnormalities in Japanese patients with Alzheimer’s disease treated with Lecanemab: A real-world study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100562
ASSESSMENT OF CLINICAL AND NEUROIMAGING EFFICACY OF TREATMENT TARGETING TAU PATHOLOGY IN MILD COGNITIVE IMPAIRMENT AND MILD TO MODERATE ALZHEIMER’S DISEASE WITH HYDROMETHYLTHIONINE MESYLATE USING EXTERNAL CONTROL DATA
Bjoern O Schelter, Helen Shiells, Serena Lo, Nafeesa Nazlee, Emily Evans, Peter Bentham, Serge Gauthier, Henrik Zetterberg, Gordon K Wilcock, Lutz Froelich, Alistair Burns, Emer MacSweeney, Clive Ballard, Jin-Tai Yu, Tay Siew Choon, Vahe Asvatourian, Natalia Muehlemann, Jan Priel, Karin Kook, Tenecia Sullivan, Diane Downie, Sonya Miller, Carol Pringle, John M?D Storey, Tom Baddeley, Charles R Harrington, Roger Staff, Anca-Larisa Sandu, Claire Hull, Richard Stefanacci, Claude M Wischik, Alzheimer\'s Disease Neuroimaging Initiative
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Hydromethylthionine mesylate (HMTM) targets tau pathology and also has tau-independent symptomatic activity. A traditional randomised placebo-controlled trial (RCT) was precluded by loss of blinding due to urinary colouration and therapeutic activity at the minimum dose required to maintain blinding.
OBJECTIVE: To evaluate the efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer’s disease (AD).
METHODS: Because a traditional RCT was not feasible without loss of blinding, we compared HMTM 16 mg/day in TRx-237–039 with propensity score matched true placebo controls from the FDA-sponsored Critical Path for AD (CPAD) database with the same inclusion/exclusion criteria (protocol TRx-237–080). We also compared HMTM 16 mg/day with matched natural history controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and with a meta-analysis of placebo arms from trials in comparable populations in analyses specified prior to the 104-week database lock of TRx-237–039.
PARTICIPANTS: Propensity score matching yielded 127 pairs (HMTM n = 127; CPAD placebo n = 127) in the CPAD comparison, and 189 pairs in the ADNI comparison. A total of 218 receiving HMTM 16 mg/day were compared with meta-analytic controls (n = 1805–8567).
INTERVENTION: HMTM 16mg/day.
MEASUREMENTS: Primary outcomes in TRx-237–080 were change from baseline to 78 weeks in ADAS-Cog13 and whole brain volume (WBV). CDR-Sum of Boxes (CDR-SB) and CDR-Global were analysed at 104 weeks. ADAS-cog11 and WBV were analysed in ADNI comparisons, and ADAS-cog11, ADCS-ADL23, CDR-SB and WBV were analysed in meta-analytic comparisons.
RESULTS: Compared with matched CPAD placebo, HMTM 16 mg/day produced statistically significant differences in change on ADAS-Cog13 (p < 0.0001) and WBV at 78 (primary; p < 0.0001) and 104 weeks (p < 0.0001), and CDR-SB differed significantly overall (104-weeks; p < 0.001) and in MCI (p = 0.007). The odds of progressing to a more advanced CDR-Global stage were lower with HMTM (overall OR 0.31) and particularly in MCI (OR 0.15) versus CPAD placebo. Clinical and brain atrophy outcomes were similarly statistically significant in comparisons with ADNI case-matched natural history data and in meta-analytic comparisons.
CONCLUSION: Comparisons of HMTM treatment with CPAD, ADNI, and meta-analytic controls provide evidence consistent with clinical benefit HMTM. It has the potential to offer an accessible oral treatment option which could be delivered with minimal patient/physician burden.
CITATION:
Bjoern O Schelter ; Helen Shiells ; Serena Lo ; Nafeesa Nazlee ; Emily Evans ; Peter Bentham ; Serge Gauthier ; Henrik Zetterberg ; Gordon K Wilcock ; Lutz Froelich ; Alistair Burns ; Emer MacSweeney ; Clive Ballard ; Jin-Tai Yu ; Tay Siew Choon ; Vahe Asvatourian ; Natalia Muehlemann ; Jan Priel ; Karin Kook ; Tenecia Sullivan ; Diane Downie ; Sonya Miller ; Carol Pringle ; John M․D Storey ; Tom Baddeley ; Charles R Harrington ; Roger Staff ; Anca-Larisa Sandu ; Claire Hull ; Richard Stefanacci ; Claude M Wischik ; Alzheimer's Disease Neuroimaging Initiative (2025): Assessment of clinical and neuroimaging efficacy of treatment targeting tau pathology in mild cognitive impairment and mild to moderate Alzheimer’s disease with hydromethylthionine mesylate using external control data. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100560
INCREASE IN HEALTHCARE UTILIZATION AND MEDICARE PAYMENT WITH PROGRESSION OF PRECLINICAL ALZHEIMER’S DISEASE
Julie Beyrer, Zachary Sheff, Nalin Payakachat, Julie M. Chandler, Yun-Fei Chen, Joanna Kubisiak, Angelina Lee, Karen C. Holdridge, Roy Yaari, Paul Aisen, Michael S. Rafii, Reisa A. Sperling, A4 and LEARN Study Teams
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) begins with the preclinical stage (Stages 1 and 2) where individuals are cognitively unimpaired but have AD pathology. Healthcare utilization and medical cost of cognitively unimpaired (preclinical) AD have not been previously evaluated.
OBJECTIVES: To describe healthcare resource utilization (HRU) and Medicare payments among cognitively unimpaired individuals with and without elevated amyloid and to evaluate the association of AD progression with HRU and Medicare payments.
DESIGN: Retrospective cohort analysis of the randomized controlled trial (Anti-Amyloid Treatment in Asymptomatic AD [A4]) and companion observational study (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [LEARN]) linked with Medicare.
SETTING: Clinical trials sites in the United States.
PARTICIPANTS: 246 cparticipants with cognitively unimpaired AD in A4 and 121 amyloid-negative participants in LEARN Medicare cohorts.
MEASUREMENTS: Measures from Medicare claims included medical conditions (diagnosis codes), HRU (inpatient, emergency room, outpatient, professional, skilled nursing facility, home health), and Medicare payments. AD progression (or cognitive or functional decline) was measured using Clinical Dementia Rating Scale-Global Score (CDR-GS) in A4/LEARN and diagnosis codes for cognitive impairment, AD, and JEN Frailty Index (JFI) of ≥6 (high frailty) in Medicare data.
RESULTS: HRU and payments were overall similar between A4 and LEARN Medicare. Claims indicators suggesting AD progression in A4 Medicare were associated with higher inpatient, outpatient, emergency room, and home health utilization (any utilization) and increased number of inpatient stays. Payments were significantly greater in A4 Medicare with AD progression vs without progression: 45% payment increase for cognitive impairment (p=0.035) with a mean incremental cost of $140 per person per month (PPPM) (95% confidence interval [CI] $125-$155), 66% payment increase for AD (p=0.011) with a mean incremental cost of $207 PPPM (95% CI $188-$226), and 103% payment increase for high frailty (p<0.001) with a mean incremental cost of $303 PPPM (95% CI $283-$323).
CONCLUSIONS: Overall, individuals with cognitively unimpaired AD in A4 Medicare did not have increased utilization and payments vs LEARN. HRU and payments were significantly greater in A4 Medicare participants with AD progression indicators in claims vs those without progression. These results highlight the need for additional research on both health and economic impacts of progression in a real-world (routine care) cohort of individuals with cognitively unimpaired AD and the potential cost savings associated with effective therapy that delays AD progression in cognitively unimpaired AD.
CITATION:
Julie Beyrer ; Zachary Sheff ; Nalin Payakachat ; Julie M. Chandler ; Yun-Fei Chen ; Joanna Kubisiak ; Angelina Lee ; Karen C. Holdridge ; Roy Yaari ; Paul Aisen ; Michael S. Rafii ; Reisa A. Sperling ; A4 and LEARN Study Teams (2025): Increase in healthcare utilization and Medicare payment with progression of preclinical Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100547
COST ANALYSES OF PLASMA P-TAU217 VERSUS P-TAU217/AΒ42 RATIO USING TWO-STEP APPROACH IN THE JAPANESE HEALTH CARE SYSTEM
Masanori Kurihara, Ryoko Ihara, Kenichiro Sato, Atsushi Iwata
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryPlasma p-tau217 may offer a cost-saving effect in diagnosing Alzheimer’s disease. However, each healthcare system has different costs, and its impact on evaluating anti-amyloid β (Aβ) therapies in Japan remains unclear. We conducted cost analyses using a two-step approach with a recently released application, assuming that measuring two analytes (p-tau217/Aβ42) would reduce the intermediate zone to 7%, despite doubling the price. Plasma biomarker costs were simulated from 100 to 800 USD. Cost savings ranged 34–79% compared with positron electron tomography (PET) and -5.6%–74% compared with in-patient cerebrospinal fluid (CSF) Aβ42/40 when 14.7% were in the intermediate zone. Savings were comparably high by measuring two analytes at 100 or 200 USD per analyte and gradually differed (one analyte better savings than two) as the cost per analyte increased. Both plasma p-tau217 and p-tau217/Aβ42 showed substantial cost-saving effects, with comparably high savings at lower costs (100, 200 USD) per analyte.
CITATION:
Masanori Kurihara ; Ryoko Ihara ; Kenichiro Sato ; Atsushi Iwata (2025): Cost analyses of plasma p-tau217 versus p-tau217/Aβ42 ratio using two-step approach in the Japanese health care system. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100572
PATHWAYS TO PARTICIPATION – A SCOPING REVIEW OUTLINING BARRIERS AND ENABLERS TO PARTICIPATION IN DEMENTIA RESEARCH
Lukas A. Duffner, Soraya Moradi-Bachiller, Dianne Gove, Ana M. Diaz-Ponce, Angela Bradshaw, Jean Georges
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Ongoing participant recruitment challenges in dementia research highlight the need to understand public perspectives on research participation. This scoping review explored existing literature on barriers and enablers to the recruitment and retention of participants in dementia studies.
METHODS: A scoping review was conducted in PubMed and PsycINFO, following the Arksey and O’Malley framework, using a keyword profile informed by a pilot search (full protocol available at osf.io/n8j4u). Abstract and full text screening were performed in duplicate and data were extracted using predefined criteria. Reported barriers and enablers were grouped into overarching themes. A panel of people with dementia and carers subsequently shared their perspectives on recruitment challenges and reflected on the review findings.
RESULTS: Forty-five publications were included for narrative synthesis, representing 112,011 participants (pooled mean age = 69.3 years; 64.8 % female). Most studies originated from the U.S. and focused on clinical dementia research, with an emphasis on recruitment rather than long-term retention. Barriers were grouped into eight themes: mistrust; fears, worries and concerns; awareness; beliefs and attitudes; practical and logistical constraints; study-related factors; informational barriers; and barriers related to carers and support systems. Enablers included internal motivators (e.g. altruism) and external facilitators (e.g. financial compensation or flexible scheduling).
CONCLUSIONS: While significant research gaps remain, many barriers to participation in dementia research appear modifiable. Targeted actions addressing these modifiable factors may enhance recruitment and retention, which may strengthen the inclusivity and impact of dementia research.
CITATION:
Lukas A. Duffner ; Soraya Moradi-Bachiller ; Dianne Gove ; Ana M. Diaz-Ponce ; Angela Bradshaw ; Jean Georges (2025): Pathways to participation – a scoping review outlining barriers and enablers to participation in dementia research. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100558
BARRIERS AND FACILITATORS TO RECRUITMENT, ENGAGEMENT, AND RETENTION OF UNDERREPRESENTED POPULATIONS IN DEMENTIA PREVENTION RESEARCH: A SCOPING REVIEW
A.F. Rirash, S. Franzen, R. Bourdage, E. Kreuk, N.C. Visser, G.M. Babulal, E. van den Berg, J.M. Papma
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryUnderrepresented populations in dementia prevention research, including minoritized racial/ethnic groups, individuals with lower socioeconomic status, and others facing social and structural disadvantages, are disproportionately affected by dementia risk. This scoping review examined barriers and facilitators to recruitment, engagement, and retention of these populations in Alzheimer’s disease and related dementias (ADRD) prevention studies, synthesizing evidence from both empirical studies and review articles. Guided by PRISMA-ScR and the conceptual structure described by Gilmore-Bykovskyi et al., findings were synthesized from 19 reviews and 53 empirical studies. Findings were interpreted with attention to how overlapping factors—such as ethnicity, age, gender, and structural inequities—may influence study participation. Studies originated primarily from the United States (U.S.). Five key themes were identified: 1) mistrust, 2) stigma and limited research literacy, 3) logistical and financial constraints, 4) communication gaps and lack of team diversity, and 5) systemic-level barriers. Facilitators included culturally tailored outreach, long-term community partnerships, and inclusive study design. Retention strategies remain underreported, and little is known about the non-U.S. context. These findings highlight the need for context-specific, multi-level strategies that address the intersecting barriers faced by underrepresented groups to support equitable participation in dementia prevention research, and ultimately, dementia prevention.
CITATION:
A.F. Rirash ; S. Franzen ; R. Bourdage ; E. Kreuk ; N.C. Visser ; G.M. Babulal ; E. van den Berg ; J.M. Papma (2025): Barriers and facilitators to recruitment, engagement, and retention of underrepresented populations in dementia prevention research: a scoping review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100557
DEMENTIA RISK FACTOR ASSESSMENT IN A LOCAL ALZHEIMER’S PREVENTION POPULATION: A GERMAN CROSS-SECTIONAL, OBSERVATIONAL STUDY
Lena Sannemann, Michelle Gerards, Lara Bohr, Frederic Brosseron, Claus Escher, Franziska Kalthegener, Theresa Müller, Alfredo Ramírez, Philip Zeyen, Frank Jessen, Ayda Rostamzadeh
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: The risk for dementia is to a significant extent driven by potentially modifiable factors. Prevention strategies are increasingly aiming at individually tailored risk reduction approaches, particularly in light of emerging Brain Health Services for dementia prevention (dBHS).
METHODS: The cross-sectional observational study “Individual Risk Profiling for Alzheimer's and Dementia Prevention” (INSPIRATION) assessed the individual risk factors of 162 participants of the local Cologne Alzheimer Prevention Registry and provided individual feedback on risk profiles during a single visit. We analysed the frequency and patterns of risk factors and explored their association with cognition and Alzheimer’s disease (AD) plasma biomarkers.
FINDINGS: The most common risk factors in this population were obesity, non-adherence to a Mediterranean diet, low subjective sleep quality, subjective experience of stress, and hearing impairment. A principal component analysis (PCA) revealed six principal components (PC), which we labeled as (1) psychosocial factors, (2) blood pressure, (3) physical condition, (4) hearing impairment, (5) lifestyle, and (6) substance use. We found isolated associations between PCs, cognition, and AD plasma biomarkers.
INTERPRETATION: These findings provide initial insights into which risk factors may be most relevant and actionable for highly-educated and prevention-motivated populations likely to seek dBHS. Interventions addressing the domains of psychosocial factors, physical condition, and lifestyle may be particularly relevant to consider for a personally tailored risk reduction approach in comparable populations.
FUNDING: The study was funded by research funds of the Medical Faculty and the University Hospital Cologne, University of Cologne and the non-profit association Kölner Verein für seelische Gesundheit e.V.
CITATION:
Lena Sannemann ; Michelle Gerards ; Lara Bohr ; Frederic Brosseron ; Claus Escher ; Franziska Kalthegener ; Theresa Müller ; Alfredo Ramírez ; Philip Zeyen ; Frank Jessen ; Ayda Rostamzadeh (2025): Dementia risk factor assessment in a local Alzheimer’s prevention population: a German cross-sectional, observational study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100556
KNOWLEDGE AND PERCEPTION OF DEMENTIA RISK AND PROTECTIVE FACTORS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Muhammed L. Sambou, Jolanda H.M. Dobbe, Elaine A.C. Albers, Kay Deckers, Lidia R. Arends, M. Arfan Ikram, Ellen M.A. Smets, Wichor M. Bramer, Jeremy A. Labrecque, Leonie N.C. Visser, Frank J. Wolters
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Optimal dementia risk reduction strategies benefit from sufficient public knowledge of risk factors and risk perception, but current public awareness is uncertain.
METHODS: In a systematic literature review on public knowledge and perception of dementia risk factors, we searched relevant databases for original research articles until 2024. When possible, we pooled study results using random effects meta-analysis, and explored sources of heterogeneity through meta-regression. Qualitative studies and studies about risk perception were analysed using narrative synthesis.
FINDINGS: Of 4996 articles screened, 155 were eligible for inclusion. Of these, 125 reported on knowledge of risk factors and 50 on risk perception, jointly providing data from 164,644 participants in 41 countries across 6 continents. Recognition of the 28 queried risk and protective factors was moderate, somewhat higher for lifestyle factors (medians: 38.5–71.5%) than for cardiovascular (9.9–66.9%) and environmental (25.4–44.4%) factors, but with large heterogeneity across queried factors. With the exception of physical activity (71.5%, IQR:46.9–88.3%), social isolation (66.6% [23.7–84.0%]) and traumatic brain injury (65.0% [18.0–76.7%]), recognition of all established modifiable risk factors for dementia from prespecified lists was below 50%, lowest for education (19.5% [7.8–54.9%]), air pollution (25.4% [16.3–41.0%]), and obesity (30.4% [27.0–43.0%]). Recall of risk factors (7 studies) was markedly lower than recognition. Meta-regression analyses showed no consistent differences by year of publication, or by participants’ age, gender, and educational attainment. Among 23 qualitative studies, limited knowledge emerged particularly regarding dementia-specific risk factors like hearing loss. Perceived risk was measured inconsistently across studies, but was generally moderate to high, along with notable worry about dementia in a large part of the older population.
CONCLUSIONS: Knowledge of dementia risk and protective factors in the general population remains limited. These findings call for population-level interventions, including educational campaigns, to enhance preventive strategies.
CITATION:
Muhammed L. Sambou ; Jolanda H.M. Dobbe ; Elaine A.C. Albers ; Kay Deckers ; Lidia R. Arends ; M. Arfan Ikram ; Ellen M.A. Smets ; Wichor M. Bramer ; Jeremy A. Labrecque ; Leonie N.C. Visser ; Frank J. Wolters (2025): Knowledge and perception of dementia risk and protective factors: a systematic review and meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100565
COMPARATIVE EFFECTS OF SOME PHARMACOLOGICAL AND NON-PHARMACOLOGICAL INTERVENTIONS ON COGNITIVE FUNCTION IN ALZHEIMER’S DISEASE: A BAYESIAN NETWORK META-ANALYSIS
Yuning Zhao, Guangxin Luo, Can Huang, Zhenyang Chen, Yu Wei, Qiaosen Chen, Fang Wang, Yong Gan, Xiaoxv Yin
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Given the growing global public health burden of Alzheimer’s disease, this study used the Bayesian network meta-analysis to assess the effects of pharmacological and non-pharmacological interventions on cognitive function in the population with Alzheimer’s disease.
METHODS: Two investigators screened the literature from English databases (PubMed, MEDLINE, Embase, Cochrane CENTRAL, and Web of Science) and three major Chinese bibliographical databases (China National Knowledge Infrastructure Database, Wanfang Database, and VIP Database). We assessed the risk of bias and publication bias of the selected literature. Subsequently, a Bayesian network meta-analysis and meta-regression were conducted to further investigate the comparative efficacy of different interventions on cognitive outcomes.
RESULTS: A total of 4788 cases were initially identified. Photobiomodulation [SMD=0.66, 95%CrI (0.29, 1.02)], enriching environment [SMD=0.69, 95%CrI (0.08, 1.31)], pharmacological therapy [SMD=0.36, 95%CrI (0.17, 0.55)], cognitive stimulation therapy [SMD=0.32, 95%CrI (0.11, 0.55)] and exercise therapy [SMD=0.28, 95%CrI (0.06, 0.51)] showed considerable enhancements in cognitive function among individuals with Alzheimer’s disease. Photobiomodulation and enriching environment stood out, with their effects more potent than those of other therapies, as indicated by the surface under the cumulative ranking curve — photobiomodulation clocked in at 87.3%, while enriching environment scored 83.8%, versus pharmacological therapy’s 54.7%.
CONCLUSIONS: Among the interventions evaluated, photobiomodulation and enriching environment were associated with better improvements in cognitive function than pharmacological therapy. Exercise therapy and cognitive stimulation therapy also demonstrated beneficial effects. Music therapy showed no statistical difference from the control group. In addition, the research developed an innovative approach to contrast pharmacological and non-pharmacological treatments for Alzheimer’s disease.
CITATION:
Yuning Zhao ; Guangxin Luo ; Can Huang ; Zhenyang Chen ; Yu Wei ; Qiaosen Chen ; Fang Wang ; Yong Gan ; Xiaoxv Yin (2025): Comparative effects of some pharmacological and non-pharmacological interventions on cognitive function in Alzheimer’s disease: A Bayesian network meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100564
ASSOCIATION OF THE CUMULATIVE MODIFIED LIFE’S ESSENTIAL 8 SCORE WITH COGNITIVE CHANGE: RESULTS FROM TWO LONGITUDINAL CO-HORTS
Yiwen Dai, Yuling Liu, Yang Pan, Menghan Zhu, Xuyang Diao, Xinqing Yang, Jingya Ma, Darui Gao, Yanyu Zhang, Mengmeng Ji, Yichi Zhang, Wuxiang Xie, Fanfan Zheng
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryINTRODUCTION: Although a higher baseline Life’s Essential 8 (LE8) score is linked to better cognitive performance and slower decline, it remains unclear whether the cumulative LE8 score is associated with cognitive change in later life.
METHODS: We included 1345 participants from the Health and Retirement Study (HRS) and 2865 participants from the English Longitudinal Study of Ageing (ELSA). A modified LE8 score was constructed based on sleep, physical activity, smoking, body mass index, blood lipids, blood glucose, and blood pressure. The cumulative modified LE8 score was calculated using 8 years of LE8 assessments. The association between cumulative modified LE8 score and cognitive change was examined using the linear mixed model.
RESULTS: Results from the HRS and the ELSA demonstrated general consistency. Pooled analysis showed that a per SD increase in cumulative modified LE8 score was associated with a slower rate of decline in global cognition (pooled Beta=0.089 SD/year), executive function (pooled Beta=0.093 SD/year), memory (pooled Beta=0.050 SD/year), and orientation (pooled Beta=0.040 SD/year).
DISCUSSION: A higher cumulative modified LE8 score was associated with better late-life cognition, highlighting the importance of maintaining long-term optimal cardiovascular health for preventing cognitive decline.
CITATION:
Yiwen Dai ; Yuling Liu ; Yang Pan ; Menghan Zhu ; Xuyang Diao ; Xinqing Yang ; Jingya Ma ; Darui Gao ; Yanyu Zhang ; Mengmeng Ji ; Yichi Zhang ; Wuxiang Xie ; Fanfan Zheng (2025): Association of the cumulative modified life’s Essential 8 score with cognitive change: Results from two longitudinal cohorts. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100548
GLOBAL, REGIONAL, AND NATIONAL BURDEN OF DEMENTIA ATTRIBUTABLE TO MOOD DISORDERS: A COMPARATIVE RISK ASSESSMENT STUDY
Jing Wu, Jiali Zhou, Shiyi Shan, Ke Tang, Longzhu Zhu, Jiayao Ying, Xinyu Liu, Peige Song
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Mood disorders, particularly depressive and bipolar disorders, have emerged as potentially modifiable risk factors for dementia. However, the burden of dementia attributable to mood disorders remains unquantified. We aimed to quantify that burden among adults aged 45 years and older using a comparative risk assessment approach.
METHODS: A literature search was performed in PubMed, Embase, and MEDLINE to identify cohort studies that assessed the association between mood disorders and subsequent dementia from database inception to 9th April 2025. Random-effects models were used to derive pooled risk ratios (RRs). Assuming a 5-year lag between mood disorders and dementia onset, we calculated population attributable fractions (PAFs) and age-standardized disability-adjusted life year (DALY) rates (ASDRs) at global, regional, and national levels. Temporal trends in ASDR were analyzed using joinpoint regression to estimate average annual percentage change.
RESULTS: 77 articles were included. The pooled RR for all-cause dementia was 1.90 (95% confidence interval [CI]: 1.70, 2.12) for depressive disorders, and 3.10 (95% CI: 2.21, 4.35) for bipolar disorder. For dementia subtypes, depressive disorders showed an association with Alzheimer’s disease (RR: 2.57, 95% CI: 2.05, 3.23), and bipolar disorder was associated with vascular dementia (RR: 3.67, 95% CI: 2.42, 5.57). In 2016, the global PAFs of dementia attributable to depressive disorders were 4.79% (95% CI: 3.19%, 6.58%) in males and 5.56% (95% CI: 3.56%, 7.84%) in females. PAFs for bipolar disorder were 1.22% (95% CI: 0.65%, 2.01%) in males and 1.34% (95% CI: 0.71%, 2.18%) in females. In 2021, the global ASDR of dementia attributable to depressive disorders was 89.61 (95% CI: 34.80, 192.24) per 100,000 population, while the global ASDR for bipolar disorder was 15.91 (95% CI: 5.56, 37.87) per 100,000 population.
CONCLUSION: Since mood disorders are a substantial contributor to dementia burden, integrating mental health management into public health policies is essential.
CITATION:
Jing Wu ; Jiali Zhou ; Shiyi Shan ; Ke Tang ; Longzhu Zhu ; Jiayao Ying ; Xinyu Liu ; Peige Song (2025): Global, regional, and national burden of dementia attributable to mood disorders: a comparative risk assessment study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2025.8
STRUCTURAL SOCIAL FACTORS MODIFY THE ASSOCIATION BETWEEN ALZHEIMER’S PATHOLOGY AND COGNITIVE FUNCTION
Michelle Gerards, Lena Sannemann, Frank Jessen
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Social factors have been linked to cognitive decline and risk of dementia. However, our understanding of their impact on cognition in the context of Alzheimer’s disease (AD) pathology is still limited.
OBJECTIVES: This study examined whether two structural social factors, relationship status (RS) and living situation (LS), modify the association between AD pathology and cognition.
DESIGN: Observational, analysis of existing cohort data.
SETTING: Data were obtained from the National Alzheimer's Coordinating Center (NACC) and the Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study.
PARTICIPANTS: Participants with available data on cognitive performance, AD pathology, and structural social factors.
MEASUREMENTS: We used the Mini-Mental State Examination (MMSE), a widely used brief screening measure of global cognitive status. For the description of AD, postmortem neuropathology (NACC) reports, or amyloid PET (IDEAS) were used. RS and LS were coded according to the respective datasets. Group comparisons and regression models were used to evaluate interactions between RS or LS with AD pathology on cognition.
RESULTS: Across cohorts, up to 31% of individuals were not in a relationship, and up to 22% lived alone. Individuals in a relationship (RS+) or those who lived with someone (LS+) showed poorer cognitive performance than those not in a relationship (RS-) or living alone (LS-) at comparable levels of AD pathology. Interaction analyses indicated that the association between AD pathology and MMSE differed by LS, with LS+ being associated with slightly lower MMSE scores across pathology levels, an effect primarily driven by participants living with someone who is not a partner. In contrast, within the NACC cohort, RS+ individuals showed overall lower MMSE scores, while the association between AD pathology and MMSE was weaker compared to RS− individuals.
DISCUSSION: LS and RS showed differences in how AD pathology related to global cognitive status. Being in a relationship was linked to a weaker association between AD pathology and global cognitive status, whereas living with someone was associated with a lower global cognitive status at comparable levels of pathology. While the direction of these associations remains unclear, our findings suggest that the relationship between AD pathology and cognitive status may vary across different structural social contexts.
CITATION:
Michelle Gerards ; Lena Sannemann ; Frank Jessen (2025): Structural social factors modify the association between Alzheimer’s pathology and cognitive function. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100563
THE ASSOCIATION BETWEEN OMEGA-3 SUPPLEMENTATION AND COGNITIVE DECLINE IN OLDER ADULTS
Zheng-Bin Liao, Zi-Cheng Hu, Gui-Hua Zeng, Jia Chen, Xin-Peng Li, Yu-Hui Liu, Xiu-Qing Yao, Ye-Ran Wang, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: While omega-3 fatty acid supplementation is widely used for cognitive protection, its efficacy remains controversial, and its impact on core Alzheimer's disease (AD) pathologies in humans is not well-established.
METHODS: This longitudinal study utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We employed linear mixed-effects models to assess the association between omega-3 supplementation and longitudinal cognitive decline, and mediation analyses to examine whether this relationship was mediated by core AD pathologies (Aβ-PET, tau-PET, T1-MRI, FDG-PET).
RESULTS: Omega-3 supplementation was associated with significantly accelerated cognitive decline, as evidenced by a faster decrease in MMSE scores (β = -0.266, p < 0.001) and a faster increase in both ADAS-Cog13 (β = 0.823, p < 0.001) and CDR-SB scores (β = 0.205, p < 0.001). This association was not mediated by Aβ deposition, tau pathology, or gray matter atrophy. Instead, longitudinal FDG hypometabolism within AD-vulnerable regions served as a significant mediating pathway, accounting for 30.8%, 40.8%, and 19.0% of the total effect on the decline in MMSE, ADAS-Cog13, and CDR-SB, respectively.
CONCLUSIONS: Omega-3 supplementation may be associated with accelerated cognitive decline in older adults, potentially through adverse effects on cerebral synaptic function rather than classical AD proteinopathies. These findings challenge the prevailing view of omega-3 as uniformly beneficial and highlight the need for a cautious reassessment of its widespread use for cognitive protection.
CITATION:
Zheng-Bin Liao ; Zi-Cheng Hu ; Gui-Hua Zeng ; Jia Chen ; Xin-Peng Li ; Yu-Hui Liu ; Xiu-Qing Yao ; Ye-Ran Wang ; Alzheimer’s Disease Neuroimaging Initiative (2025): The association between omega-3 supplementation and cognitive decline in older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100569
SPEECH-BASED DIGITAL BIOMARKERS FOR EARLY ETIOLOGICAL STRATIFICATION OF ALZHEIMER’S DISEASE AND FRONTOTEMPORAL DEGENERATION: A BIOMARKER-CONFIRMED PROSPECTIVE STUDY
Eloïse Da Cunha, Valeria Manera, Frédéric Chorin, Justine Lemaire, Alexandra Plonka, Aurélie Mouton, Raphaël Zory, Auriane Gros
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Early differentiation between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) is a prerequisite for secondary prevention and targeted trial enrollment, yet remains challenging at disease onset. We investigated whether automated speech analysis could serve as a digital biomarker for early etiological stratification across clinically heterogeneous presentations.
METHODS: In this prospective biomarker-confirmed prognostic study, 172 participants (108 patients with biomarker-confirmed AD or FTLD and 64 controls) completed a standardized speech protocol at initial clinical assessment. Acoustic, temporal, and phonatory features were automatically extracted. Machine learning models and a stacking ensemble were trained using stratified, repeated 5-fold cross-validation to discriminate between AD and FTLD pathology, with exploratory analysis extending to atypical and rare phenotypes crossed with physiopathology, including primary progressive aphasia (PPA) variants.
RESULTS: Speech-based models achieved high sensitivity and specificity in distinguishing physiopathology independently (mean area under the curve (AUC)=0.986) and crossed phenotype and physiopathological diagnostic association (mean AUC=0.966).The ensemble identified 82% of cases with clinicopathological discordance. Interpretability analyses revealed distinct speech signatures: AD was associated with global speech slowing and phonatory instability, while FTLD was characterized by reduced verbal output and acoustic hypo-expressivity.
CONCLUSIONS: Automated speech analysis provides a promising non-invasive digital biomarker for the early etiological stratification of AD and FTLD, including atypical phenotypes, with high accuracy in a monocentric biomarker-confirmed cohort. These findings support the feasibility of speech-based etiological stratification and its potential to complement existing biomarker frameworks, particularly in cases of clinicopathological discordance. External validation is required before clinical deployment can be considered.
CITATION:
Eloïse Da Cunha ; Valeria Manera ; Frédéric Chorin ; Justine Lemaire ; Alexandra Plonka ; Aurélie Mouton ; Raphaël Zory ; Auriane Gros (2025): Speech-based digital biomarkers for early etiological stratification of Alzheimer’s disease and frontotemporal degeneration: a biomarker-confirmed prospective study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100573
AMYLOID PATHOLOGY AND MODIFIABLE RISK FACTORS IN COGNITIVE DECLINE AMONG COGNITIVELY UNIMPAIRED OLDER ADULTS
Ying-Hsin Hsu, Chih-Kuang Liang, Ming-Yueh Chou, Jaysón Davidson, Yu-Chun Wang, Mike A. Nalls, Luigi Ferrucci, Mark Cookson, Hirotaka Iwaki
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) pathology, particularly amyloid-β (Aβ) deposition, occurs years before clinical symptoms. Modifiable risk factors may influence cognitive trajectories during this preclinical stage, but whether amyloid status alters their effects remains unclear.
OBJECTIVES: To investigate interactions between amyloid pathology and modifiable risk factors in predicting longitudinal cognitive decline among cognitively unimpaired older adults.
DESIGN AND SETTING: This study was a secondary analysis of data derived from two large multicenter longitudinal cohort studies, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study.
PARTICIPANTS: A total of 1707 cognitively unimpaired adults aged 65–85 years were included, comprising 1169 amyloid-positive participants from the A4 Study (Aβ+) and 538 amyloid-negative participants from the LEARN Study (Aβ–).
MEASUREMENTS: Cognitive function was assessed every six months using the Preclinical Alzheimer’s Cognitive Composite (PACC) over a mean follow-up of 4.9 years. Eight established modifiable risk factors—low education, alcohol use, diabetes, high cholesterol, high blood pressure, obesity, depressive symptoms, and physical inactivity—were evaluated. Linear mixed-effects models were applied to examine associations between each risk factor and longitudinal PACC decline, and to test interactions with amyloid status, adjusting for demographic and genetic covariates.
RESULTS: Significant interactions between amyloid status and modifiable risk factors were observed for diabetes (adjusted β = −0.206, p = 0.032), high cholesterol (adjusted β = −0.155, p < 0.001), and physical inactivity (adjusted β = −0.161, p = 0.046), indicating combined effects rather than additive effects on cognitive decline among Aβ+ individuals. In the A4 study (Aβ+), low education, diabetes, high cholesterol, and physical inactivity were independently associated with accelerated cognitive decline, whereas obesity was linked to slower decline. In contrast, in the LEARN study (Aβ-), these associations were not statistically significant.
CONCLUSIONS: In conclusion, the significant interactions with amyloid status were observed for diabetes, high cholesterol, and physical inactivity, indicating that these risk factors were associated with faster cognitive decline specifically in Aβ+ individuals. The results suggest that consideration of amyloid status may be important when evaluating the potential role of metabolic and lifestyle risk factors in preclinical cognitive decline. In Aβ+ individuals, obesity was associated with slower cognitive decline, while low education was linked to lower baseline cognition or a reduced symptom threshold, without a significant interaction with amyloid status. Future studies should incorporate amyloid status and longitudinal biomarkers to assess whether modifying these factors can slow preclinical cognitive decline.
CITATION:
Ying-Hsin Hsu ; Chih-Kuang Liang ; Ming-Yueh Chou ; Jaysón Davidson ; Yu-Chun Wang ; Mike A. Nalls ; Luigi Ferrucci ; Mark Cookson ; Hirotaka Iwaki (2025): Amyloid pathology and modifiable risk factors in cognitive decline among cognitively unimpaired older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100574
ASSOCIATIONS OF PLASMA BIOMARKERS WITH AGE IN THE PRESENILIN-1 E280A AUTOSOMAL DOMINANT ALZHEIMER\'S DISEASE KINDRED
Vincent Malotaux, Vivian Ku, Paula Ospina Lopera, Yi Su, Yinghua Chen, Alpana Singh, Jonathan Ruiz-Triviño, María José Hidalgo, Laura Osorio, Laura Serna, Daniela Giraldo, Diana Alzate, Bing He, Catarina Tristão-Pereira, Liliana Ramirez Gomez, Sonia Do Carmo, A. Claudio Cuello, Nicholas J. Ashton, Eric M. Reiman, David Aguillón, Yakeel T. Quiroz
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Autosomal-dominant Alzheimer’s disease (ADAD) offers a model to define early biological changes in Alzheimer’s disease due to its predictable age at symptom onset. Although ultrasensitive plasma assays are available, their associations with age in ADAD remain incompletely characterized.
OBJECTIVES: To characterize age-related changes in plasma biomarkers and examine associations with cognition in PSEN1 E280A ADAD.
DESIGN AND SETTING: Cross-sectional observational study in members of the Colombian PSEN1 E280A kindred.
PARTICIPANTS: A total of 164 individuals were included, comprising 83 mutation carriers (mean age 34.36±9.82 years; 54% female) and 81 non-carriers (mean age 33.75±9.84 years; 52% female).
MEASUREMENTS: Plasma Aβ42/Aβ40, phospho-tau217 (p-tau217), brain-derived tau (BD-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were quantified. Sex-adjusted associations with age, divergence ages between groups, classification performance (ROC curves), and associations with cognition (MMSE and CERAD delayed recall) were assessed.
RESULT: All plasma biomarkers were associated with age (p < .01). Divergence between carriers and non-carriers began with Aβ42/Aβ40 before age 18, followed by p-tau217 (26.0 years), GFAP (26.1 years), BD-tau (27.9 years), and NfL (38.7 years). Aβ42/Aβ40 showed the highest discrimination of mutation status (AUC=0.99), followed by p-tau217 (AUC=0.87) and GFAP (AUC=0.84). Among carriers, p-tau217, GFAP, BD-tau, and NfL were associated with MMSE, while p-tau217, GFAP, and NfL predicted CERAD delayed recall.
CONCLUSION: Plasma biomarkers exhibit a temporal cascade in PSEN1 E280A ADAD. P-tau217 and GFAP show the strongest associations with early cognitive decline, suggesting their potential utility for tracking disease progression and monitoring treatment effects in E280A carriers.
CITATION:
Vincent Malotaux ; Vivian Ku ; Paula Ospina Lopera ; Yi Su ; Yinghua Chen ; Alpana Singh ; Jonathan Ruiz-Triviño ; María José Hidalgo ; Laura Osorio ; Laura Serna ; Daniela Giraldo ; Diana Alzate ; Bing He ; Catarina Tristão-Pereira ; Liliana Ramirez Gomez ; Sonia Do Carmo ; A. Claudio Cuello ; Nicholas J. Ashton ; Eric M. Reiman ; David Aguillón ; Yakeel T. Quiroz (2025): Associations of plasma biomarkers with age in the presenilin-1 E280A autosomal dominant Alzheimer's disease kindred. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100578
MULTIDIMENSIONAL MODELING OF BIOLOGICAL AGING: INTEGRATING GAIT, EYE MOVEMENT, REST-STATE FUNCTIONAL CONNECTIVITY, AND PLASMA BIOMARKERS IN NON-DEMENTIA OLDER ADULTS
Jingyi Lin, Yiliang Liu, Ziyu Ouyang, Xuan Yang, Sizhe Zhang, Tianyan Xu, Qijie Yang, Yuan Zhu, Meidan Wan, Xuewen Xiao, Xiangmin Fan, Beisha Tang, Lu Shen, Bin Jiao, Shilin Luo
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryAccurate modeling of biological age has clinical value for risk stratification, personalized prevention, and intervention planning, promoting proactive healthcare for aging and age-related diseases. Because aging is multidimensional, robust and interpretable multimodal approaches are needed. We studied 908 non-dementia older adults (> 60 years), collecting data on gait, eye movements, resting-state functional connectivity (rs-FC), and plasma biomarkers (neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP). Fourteen gait features, two eye movement features, 19 rs-FC features, and plasma GFAP levels were significantly correlated with age (p < 0.05). Among single-domain models, eye movement features showed the strongest predictive performance (R2 = 0.606; MAE = 3.060). A combined multimodal model achieved markedly higher accuracy (R2 = 0.814; MAE = 1.902). These findings demonstrate that integrating physiological, neurological, and biomarker data substantially improves biological age modeling, supporting the development of comprehensive frameworks to assess aging better and guide timely, targeted preventive strategies.
CITATION:
Jingyi Lin ; Yiliang Liu ; Ziyu Ouyang ; Xuan Yang ; Sizhe Zhang ; Tianyan Xu ; Qijie Yang ; Yuan Zhu ; Meidan Wan ; Xuewen Xiao ; Xiangmin Fan ; Beisha Tang ; Lu Shen ; Bin Jiao ; Shilin Luo (2025): Multidimensional modeling of biological aging: integrating gait, eye movement, rest-state functional connectivity, and plasma biomarkers in non-dementia older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100566
THE CONCURRENT BURDEN OF ALZHEIMER’S PATHOLOGY, CEREBRAL AMYLOID ANGIOPATHY, AND MICROINFARCTS ON COGNITIVE DECLINE
Mingyao You, Chao Tang, Lianfei Liu, Dengpeng Chen, Yillin Wu, Dian He
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) is frequently complicated by vascular co-morbidities. However, the specific mechanistic pathways by which vascular lesions interact with genetic susceptibility to accelerate cognitive decline remain unclear. This study investigated whether cerebral amyloid angiopathy (CAA) and cortical microinfarcts mediate the impact of AD pathology on cognition and evaluated the modifying role of APOE genotype.
METHODS: We conducted a retrospective clinico-pathological study using the National Alzheimer’s Coordinating Center (NACC) database. The cohort included autopsy-confirmed participants aged 50 and older. Structural Equation Modeling (SEM) was employed to quantify the pathways linking AD pathology (Thal phase) to CAA severity, microinfarcts, and cognitive performance (CDR-Sum of Boxes). We further assessed the cumulative burden of pathology by comparing "Pure AD" cases against those with a "Triple Hit" of AD, CAA, and microvascular injury.
RESULTS: SEM analysis identified a significant statistical mediation pathway wherein parenchymal amyloid is strongly associated with CAA, which correlates with an increased risk of microinfarcts and subsequent cognitive dysfunction. We observed a significant gene-pathology interaction: APOE ε4 carriers demonstrated a steeper trajectory of cognitive decline for a given severity of CAA compared to non-carriers. Furthermore, the "Triple Hit" group exhibited significantly worse cognitive impairment than the "Pure AD" group (P < 0.001), independent of age and education.
CONCLUSIONS: Vascular pathology is a critical mediator of cognitive failure in AD, particularly in APOE ε4 carriers. The concurrent "Triple Hit" of proteinopathy and vasculopathy is associated with a profound failure of cognitive reserve, likely reflecting a more advanced global disease state. These findings highlight the urgent need to target vascular resilience as a disease-modifying strategy in Alzheimer’s disease.
CITATION:
Mingyao You ; Chao Tang ; Lianfei Liu ; Dengpeng Chen ; Yillin Wu ; Dian He (2025): The concurrent burden of Alzheimer’s pathology, cerebral amyloid angiopathy, and microinfarcts on cognitive decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100568
DEPRESSIVE SYMPTOMS AS A RISK FACTOR OR PRODROME OF DEMENTIA: MULTI-STATE COGNITIVE TRANSITIONS MODIFIED BY AGE AND POLYGENIC RISK
Ziyang Ren, Ruyi Zhang, Shuai Guo, Yihao Zhao, Jufen Liu, Xiaoying Zheng
J Prev Alz Dis 2026;6(13)
Show summaryHide summaryBACKGROUND: Whether depressive symptoms signal a risk factor or a prodromal symptom of dementia, and how this depends on age, genetic susceptibility, and cognitive stages, remains controversial.
OBJECTIVES: To examine the association between depressive symptoms and incident dementia and cognitive transitions, and to test effect modification by age and AD genetic susceptibility (APOE and AD polygenic risk score [PRS]).
DESIGN: Longitudinal cohort study (1998–2020) using repeated assessments; incident dementia was modeled using Fine-Gray competing-risk models, and cognitive transitions were modeled with multi-state Markov models.
SETTING: The U.S. Health and Retirement Study.
PARTICIPANTS: For the main incident dementia analysis, 13,225 dementia-free participants were included at baseline; genetic and repeated-measures analyses were restricted to 12,089 participants with complete PRS/APOE data.
MEASUREMENTS: Depressive symptoms were assessed with the 8-item CES-D. Cognitive status was classified as normal cognition, subjective memory complaint (SMC), cognitive impairment no dementia (CIND), or dementia. AD genetic susceptibility was indexed by APOE and AD PRS. Outcomes included incident dementia and transitions across cognitive states.
RESULTS: Baseline depressive symptoms (prevalence 11.3%) were associated with a higher incidence of dementia (sHR 1.24, 95% CI 1.10–1.39), with stronger associations in late midlife (50–59y: sHR 1.65) than ≥60y (sHR 1.19; P for interaction=0.001). After excluding dementia occurring within 5–10y, the associations for late midlife (but not ≥60y) remained significant (sHR for 5y=1.57; for 10y=1.55, both P for interaction≤0.030). AD PRS modified this association: depressive symptoms predicted dementia only among individuals with lower AD PRS, whereas APOE ε4 showed no modification. Multi-state analyses showed depressive symptoms accelerated progression across the cognitive continuum (e.g., normal cognition → SMC, HR=1.49; SMC → CIND, HR=1.33; CIND → dementia, HR=1.17) and reduced reversion to normal cognition. Furthermore, AD genetic susceptibility was positively associated with depressive symptom burden, specifically at the SMC stage.
CONCLUSIONS: Depressive symptoms in late midlife, especially with lower AD PRS, are more consistent with a potentially modifiable risk marker for dementia, whereas depressive symptoms emerging at SMC in genetically susceptible adults may more often reflect prodromal disease activity.
CITATION:
Ziyang Ren ; Ruyi Zhang ; Shuai Guo ; Yihao Zhao ; Jufen Liu ; Xiaoying Zheng (2025): Depressive symptoms as a risk factor or prodrome of dementia: multi-state cognitive transitions modified by age and polygenic risk. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100577
LETTER TO THE EDITOR: HEALTH-ECONOMIC CHALLENGES FOR NEW ALZHEIMER’S DISEASE TREATMENTS
Jinjing Fu, Anders Sköldunger, Angela Bradshaw, Hana Marie Broulíková, Chiara C Brück, Jack M. Chapel, Sabine Grimm, Anna Hansson, William L. Herring, Jakub Hlávka, Men Thi Hoang, Linus Jönsson, Filipa Landeiro, Javier Mar, Alison McKean, Matej Misik, Peter Neumann, Thomas Rapp, Craig Ritchie, Anja Schiel, Yi Sun, Dominic Trépel, David Trueman, P.J. van der Veere, Lynn van Rosmalen, Jean L Vonsy, Lizzie Walker, Anders Wimo, Bengt Winblad, Xin Xia, Ron Handels
J Prev Alz Dis 2026;6(13)
Show summaryHide summary
CITATION:
Jinjing Fu ; Anders Sköldunger ; Angela Bradshaw ; Hana Marie Broulíková ; Chiara C Brück ; Jack M. Chapel ; Sabine Grimm ; Anna Hansson ; William L. Herring ; Jakub Hlávka ; Men Thi Hoang ; Linus Jönsson ; Filipa Landeiro ; Javier Mar ; Alison McKean ; Matej Misik ; Peter Neumann ; Thomas Rapp ; Craig Ritchie ; Anja Schiel ; Yi Sun ; Dominic Trépel ; David Trueman ; P.J. van der Veere ; Lynn van Rosmalen ; Jean L Vonsy ; Lizzie Walker ; Anders Wimo ; Bengt Winblad ; Xin Xia ; Ron Handels (2025): Letter to the Editor: Health-economic challenges for new Alzheimer’s disease treatments. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100575