08/2026 journal articles
EDITORIAL: TAU-ING AND FRO-ING: THE TANYCYTIC SHUTTLE IN NEURODEGENERATION
Vincent Prévot, Markus Schwaninger, Ruben Nogueiras, S. Rasika
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryAfter more than a century since Alzheimer's disease (AD) was described and decades of research into β-amyloid and Tau proteins, mechanisms underlying pathogenic protein clearance from brain remain poorly understood. Recent research identifies tanycytes—specialized hypothalamic cells lining the third ventricle—as a previously unrecognized clearance system for brain Tau. These cells actively transport Tau from cerebrospinal fluid to blood via pituitary portal circulation but are dramatically fragmented in AD brains. Single-nucleus RNA sequencing reveals altered stress and transport gene expression in AD tanycytes, while functional studies show disrupted tanycytic transport reduces Tau efflux and exacerbates pathology. Beyond protein clearance, tanycytes maintain critical metabolic and neuroendocrine pathways influencing cognition. Their unique blood-brain interface position makes them attractive therapeutic targets. As transcriptomic evidence suggests tanycytes are hotspots for age-related changes, their dysfunction may herald "tanycytopathies" underlying multiple neurodegenerative disorders.
CITATION:
Vincent Prévot ; Markus Schwaninger ; Ruben Nogueiras ; S. Rasika (2026): Editorial: Tau-ing and fro-ing: the tanycytic shuttle in neurodegeneration. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100643
EDITORIAL : IS IT TIME TO MAKE BRAIN HEALTH A VITAL SIGN?
Gregory Cooper
J Prev Alz Dis 2026;8(13)
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CITATION:
Gregory Cooper (2026): Editorial: Is it time to make brain health a vital sign?. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100654
EDITORIAL: FROM TRIAL POPULATION TO TREATED POPULATION: WHY EU-ELIGIBLE SUBGROUP ANALYSES MATTER FOR ANTI-AMYLOID IMMUNOTHERAPY
Timo Grimmer
J Prev Alz Dis 2026;8(13)
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CITATION:
Timo Grimmer: From trial population to treated population: why EU-eligible subgroup analyses matter for anti-amyloid immunotherapy. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.1016/j.tjpad.2026.100665
EDITORIAL: DIETARY PATTERNS FOR COGNITIVE HEALTH: BRIDGING EVIDENCE ACROSS EAST AND WEST
Lei Feng
J Prev Alz Dis 2026;8(13)
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CITATION:
Lei Feng ; ; (2026): Dietary patterns for cognitive health: bridging evidence across east and west. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://dx.doi.org/10.1016/j.tjpad.2026.100663
SUBOPTIMAL ADHERENCE TO BRAIN HEALTH RECOMMENDATIONS IN PATIENTS PURSUING ANTI-AMYLOID ANTIBODY THERAPY FOR ALZHEIMER’S DISEASE: REPORT FROM THE BRAIN HEALTH VITAL SIGNS PROJECT
Kirk R Daffner, Kayla Riera, George R Ghorayeb, Brittany M McFeeley, Emma Weizenbaum, Kim Willment, Seth A Gale
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND: Consensus is consolidating around a set of lifestyle and medical factors that can promote brain health and reduce the risk of dementia for older adults and further decline for those with early Alzheimer's disease (AD) and related disorders. Little is known about the degree to which recommended brain-healthy behaviors have been adopted by patients with early AD pursuing anti-amyloid antibody therapy (AAT), a proactive group interested in doing what is under their control to help preserve cognitive and functional status. Here, initial results of a clinically relevant quality improvement study are reported.
OBJECTIVE: To determine the extent to which patients pursuing AAT for AD adhere to consensus-based brain health recommendations.
PARTICIPANTS: One hundred fifty patients with mild cognitive impairment (MCI) or mild dementia due to AD seeking AAT were studied and compared to a group of 117 patients with MCI or mild dementia who were not pursuing AAT.
MEASUREMENTS: Using a clinical survey tool developed for the project, patients were assessed on 15 modifiable risk factors for cognitive decline and dementia, including 11 via e-survey (diet, physical activity, cognitive activity, sleep, social engagement, smoking status, alcohol consumption, hearing, vision, mood/stress, and purpose in life) and 4 via electronic medical record (EMR) (blood pressure, BMI, LDL cholesterol level, and HbA1c). For each factor, the percentage of each of the two patient groups that was not optimally adhering to brain health-related guidelines was calculated. For each individual, the total number of factors not optimally being followed was determined.
RESULTS: Less than 3% of patients with early AD pursuing AAT were following or had anthropometric measures/lab values in line with all 15 brain health recommendations. The five factors with the lowest adherence rates involved physical activity, mood/stress, HbA1c, blood pressure, and BMI, with 44–63% of the AAT group suboptimally following consensus-based guidelines. For 11 of 15 factors, >25% of the group were not adhering to guidelines. No robust differences in degree or pattern of adherence to guidelines were observed between patients pursuing and not pursuing AAT. There were no data in the EMR for HbA1c in >42% of patients and for LDL in >23% of patients in either group.
CONCLUSIONS: Suboptimal adherence to brain health recommendations may be common among patients with early AD, whether they are pursuing AAT or not. These results suggest that healthcare systems may need to develop more effective strategies and individualized interventions for addressing modifiable risk factors for cognitive decline and dementia, and more efficacious procedures for ensuring that relevant, actionable data associated with brain health are updated in the EMR.
CITATION:
Kirk R Daffner ; Kayla Riera ; George R Ghorayeb ; Brittany M McFeeley ; Emma Weizenbaum ; Kim Willment ; Seth A Gale (2026): Suboptimal adherence to brain health recommendations in patients pursuing anti-amyloid antibody therapy for Alzheimer’s disease: Report from the Brain Health Vital Signs project. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100640
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
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND: 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
LETTER TO THE EDITOR: THE GENERALIZABILITY GAP: ANTICOAGULANT EXCLUSIONS AND THE \"ENHANCED SAFETY\" OF DONANEMAB IN THE EU-ELIGIBLE POPULATION
Azan Ijaz, Ghulam Mohyudin
J Prev Alz Dis 2026;8(13)
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CITATION:
Azan Ijaz ; Ghulam Mohyudin (2026): Letter to the Editor: The generalizability gap: anticoagulant exclusions and the "Enhanced Safety" of donanemab in the EU-eligible population. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100628
DIETARY PATTERNS AND ALZHEIMER\'S DISEASE: EAST-WEST PERSPECTIVES AND FUTURE INTERVENTION STRATEGIES
Wanlu Jiang, Yijia Lin, Qihao Guo, Ya Miao
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryAmong various modifiable risk factors, dietary patterns (DPs), as a holistic lifestyle intervention, have become a focus of current research due to their protective effects on cognitive health. Classic Western DPs, such as the Mediterranean diet (MedDiet), have been widely confirmed to effectively improve cognitive function, thereby reducing the risk of Alzheimer's disease (AD). However, existing evidence mainly concentrates on Western populations and their DPs, including the MODERN (Machine learning-assisted Optimizing Dietary intERvention against demeNtia risk) diet optimized using machine learning. Given the significant differences in food types, dietary habits, and cooking methods among Asian populations, research on localized DPs optimized for cognitive health in Asian populations remains insufficient. In this context, the team at the Department of Geriatrics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine has taken the lead in systematically defining the Shanghai Cognitive Diet Pattern (SCDP). This review aims to comprehensively outline the core features and potential biological mechanisms relevant to AD in both classic Western DPs and the emerging East Asian DP. Subsequently, this review will systematically compare Eastern and Western DPs. In conclusion, this review proposes shifting dietary strategies from population-level adaptation to individual precision, in conjunction with multimodal lifestyle management, and offers novel strategies for the prevention and management of AD.
CITATION:
Wanlu Jiang ; Yijia Lin ; Qihao Guo ; Ya Miao (2026): Dietary patterns and Alzheimer's disease: East-west perspectives and future intervention strategies. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2026.100636
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
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryPreclinical 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
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
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND: 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
BIDIRECTIONAL CAUSAL RELATIONSHIPS BETWEEN PLASMA PROTEINS, NEUROIMAGING METRICS AND RISK OF ALZHEIMER\'S DISEASE
Xu Xu, Lintong Li, Wei Huang, Ying Yang, Xu Li, Pei Wang, Mengmeng Zhao, Huiliang Zhang, Chaoming Yuan
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND: Changes in neuroimaging metrics are among the first detectable pathophysiological alterations in Alzheimer's disease (AD). Proteins are closely linked to fluctuations in neuroimaging metrics. Therefore, the analysis of the proteomic signature associated with neuroimaging metrics holds significant promise for uncovering therapeutic targets that contribute to AD.
METHODS: GWAS data concerning the Brain Imaging Data Structure (BIDs). The AD cohort comprised a total of 401,661 individuals diagnosed with AD, alongside 10,520 control participants. For a bidirectional MR analysis involving neuroimaging metrics, proteomics, and AD, the methods utilized included inverse variance weighted (IVW), MR Egger, weighted median, weighted mode, and the Wald ratio approaches.
RESULTS: We identified 12 neuroimaging metrics that demonstrate significant relevance to AD (thickness of the left total hemisphere, volume of the right thalamus, and et al.). These metrics are structural magnetic resonance imaging (MRI) biomarkers that remain stable throughout the entire course of AD, from the preclinical stage through mild cognitive impairment (MCI) to dementia. Additionally, we found a substantial number of 1633 proteins that also show a noteworthy causal relationship with AD. Functional enrichment analysis indicated that these proteins were predominantly focused within various pathways linked to AD, encompassing those involved in the synaptic vesicle cycle, synaptic membranes, neurotransmitter release, and the activity of GABA receptors. In addition, our research indicates that the significant relationships observed between the identified proteins and AD are influenced by neuroimaging metrics. Notably, we found that these neuroimaging metrics play a crucial role in mediating a substantial 67% of the inverse relationship that exists between PTPRC and the phenotypic characteristics associated with AD.
CONCLUSIONS: This study successfully establishes a connection between proteomic and neuroimaging metrics, as well as the AD that influence them. By creating this relationship, the research offers important information that aids in comprehending the intricate mechanisms involved in AD.
CITATION:
Xu Xu ; Lintong Li ; Wei Huang ; Ying Yang ; Xu Li ; Pei Wang ; Mengmeng Zhao ; Huiliang Zhang ; Chaoming Yuan (2025): Bidirectional causal relationships between plasma proteins, neuroimaging metrics and risk of Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100619
THE TIME INTERVAL FROM AMYLOID TO TAU PET POSITIVITY VARIES BY AGE, SEX AND APOE-Ε4 STATUS
Marta Milà-Alomà, Isabella Hausle, Kellen K. Petersen, Pamela Thropp, Suzanne E. Schindler, Duygu Tosun, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) progression varies widely among individuals. Identifying factors influencing timing of pathology and clinical progression is crucial for optimizing early intervention trials.
OBJECTIVES: To investigate how the estimated age at amyloid and tau PET positivity, and the time interval between these two key events (“amyloid–tau time interval”), relate to symptom onset and clinical progression, and to assess the effects of APOE-ε4 status and sex on these associations.
DESIGN: This analysis used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Harvard Aging Brain Study (HABS).
SETTING: The ADNI is a multicenter observational cohort conducted at 55 sites across the United States; The HABS is a longitudinal, single-center observational cohort.
PARTICIPANTS: This study included participants with at least one positive amyloid PET scan (ADNI n = 792; HABS n = 104) or at least one positive tau PET scan (ADNI n = 212; HABS n = 48). All participants had information on sex, APOE-ε4 status, and longitudinal cognitive assessments.
MEASUREMENTS: We examined the influence of APOE-ε4 status, sex, and their interaction on the estimated age at biomarker positivity and the amyloid-tau time interval. Accelerated Failure Time (AFT) models were used to predict time to symptom onset (CDR > 0) based on estimated biomarker positivity age and the amyloid-tau time interval. Linear mixed-effects (LME) models evaluated differences in the rate of cognitive decline, as measured by CDR-SB, over five years following symptom onset according to estimated biomarker positivity age and amyloid-tau time interval. Additional models included interaction terms with sex or APOE-ε4 status.
RESULTS: The amyloid-tau time interval varied markedly between individuals and was shorter in APOE-ε4 carriers, women, and those with older age at amyloid PET positivity. APOE-ε4 carriers and women became amyloid and tau PET positive at younger ages. Following amyloid PET positivity, a shorter time to tau PET positivity predicted earlier symptom onset. After symptom onset, faster cognitive decline was observed in individuals with younger ages at amyloid or tau PET positivity. The time to symptom onset following tau PET positivity, or the rate of cognitive decline after symptom onset, were not influenced by the amyloid-tau time interval.
CONCLUSIONS: After becoming amyloid PET positive, APOE-ε4 carriers, women and older individuals may have a shorter window for detection and treatment before they become tau PET positive and develop symptoms. These findings should guide the identification of individuals at highest risk of rapid AD progression, enabling more efficient participant selection for clinical trials.
CITATION:
Marta Milà-Alomà ; Isabella Hausle ; Kellen K. Petersen ; Pamela Thropp ; Suzanne E. Schindler ; Duygu Tosun ; Alzheimer’s Disease Neuroimaging Initiative (2025): The time interval from amyloid to tau PET positivity varies by age, sex and APOE-ε4 status. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100622
TAILORED IMPLEMENTATION OF MULTIDOMAIN INTERVENTION TO PREVENT COGNITIVE IMPAIRMENT IN COMMUNITY-DWELLING OLDER ADULTS (TIMI-COG): A STUDY PROTOCOL FOR A HYBRID TYPE 2 TRIAL EFFECTIVENESS-IMPLEMENTATION STUDY
Zishuo Huang, Changmiao Shi, Erxu Xue, Gonghang Qiu, Yurong Jing, Ziyi Wang, Xinhua Ao, Dong (Roman) Xu, Ying Wang
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND & OBJECTIVES: Despite growing recognition of multidomain non-pharmaceutical interventions (NPIs) for preventing cognitive impairment, their scalable implementation remains underdeveloped in China. This hybrid type 2 effectiveness-implementation study aims to bridge this gap by identifying implementation determinants, developing tailored strategies, and evaluating both implementation or health outcomes for multidomain NPIs and tailored strategies.
METHODS: This protocol describes the design of an ongoing study. The formative phase has been completed: guided by Consolidated Framework for Implementation Research (CFIR), we integrated the COM-B model from the Behaviour Change Wheel (BCW) and the Theoretical Domains Framework (TDF) into an interview guide. Key informant interviews and focus groups identified barriers/facilitators, and the CFIR-ERIC matching tool finalized the implementation strategies. Subsequently, a hybrid type 2 cluster RCT will be conducted (or is currently underway) across 13 districts in Changxing County, Zhejiang. A total of 1170 older adults and 273 community health workers (CHWs) - including general practitioners, social workers, and volunteers - will be randomized into three study arms: Arm 1 will receive evidence-based practices (EBP) combined with intrinsic motivation; Arm 2, EBP with implementation strategies; and Arm 3 (control), health education with implementation strategies. The EBP package includes cardio-metabolic risk management, cognitive training, physical activity, and nutritional counseling. Implementation uses three bundles: (1) Capacity Building and Professional Support, (2) Collaborative Implementation and Network Building, and (3) an AI-enabled WeChat mini-program (Timi-Cog). Outcomes will be assessed using the Re-AIM framework over 18 months. Statistical analysis will employ mixed-effects linear models, adjusted for baseline characteristics and clustering effects.
CONCLUSIONS & IMPLICATIONS: This theory-informed initiative addresses the dementia prevention implementation gap in China. By combining BCW/TDF frameworks with implementation science methods and employing a hybrid design, the study will generate robust evidence on both clinical effectiveness and practical implementation, informing the integration of multidomain NPIs into China’s primary care system.
CITATION:
Zishuo Huang ; Changmiao Shi ; Erxu Xue ; Gonghang Qiu ; Yurong Jing ; Ziyi Wang ; Xinhua Ao ; Dong (Roman) Xu ; Ying Wang (2025): Tailored implementation of multidomain intervention to prevent cognitive impairment in community-dwelling older adults (Timi-Cog): A study protocol for a hybrid type 2 trial effectiveness-implementation study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100623
COMBINED EFFECT OF ANXIETY DISORDER AND INSOMNIA ON THE RISK OF INCIDENT ADRD DIAGNOSIS
SangNam Ahn, Joanne Salas, Jinmyoung Cho, Jeffrey F. Scherrer
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND: 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
DRAWING A LINE: DIFFERENTIATING MILD FROM MODERATE DEMENTIA USING THE FUNCTIONAL ACTIVITIES QUESTIONNAIRE
Ersin Ersözlü, Lukas Preis, Aykut Aktuz, Louise Droste, Akin Erman, Daria Gref, Julian Hellmann-Regen, Katharina Sophie Strentz
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND: Accurate differentiation between mild and moderate dementia is increasingly important, particularly as amyloid-targeting therapies are restricted to early disease stages. Functional impairment in instrumental activities of daily living is a hallmark of progression beyond mild dementia. The informant-based Functional Activities Questionnaire (FAQ) is widely used, but empirically validated cut-offs distinguishing mild from moderate dementia remain insufficiently defined.
METHODS: The optimal cut-off score was derived from the entire National Alzheimer’s Coordinating Center (NACC) Uniform Data Set as a discovery cohort (n = 34,513) and validated in two independent multicentric cohorts (Alzheimer’s Disease Neuroimaging Initiative (ADNI) n = 381 and Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) n = 74). The dementia staging was based on the Clinical Dementia Rating (CDR) global score. Functional impairment was assessed using the 10-item FAQ. Receiver operating characteristic analyses in NACC identified optimal thresholds, which were applied unchanged in validation cohorts. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated, and discordant cases were examined to identify factors associated with misclassification.
RESULTS: In NACC, the FAQ demonstrated excellent discrimination of moderate dementia (AUC=0.947, 95% CI 0.944–0.949). A cut-off value of ≥18 maximized discrimination (sensitivity 96%, specificity 87%). A higher threshold of ≥23 improved specificity (92%), while maintaining sensitivity (83%). In ADNI and FTLDNI, the sensitivity of ≥18 threshold yielded 92% and 94%, respectively. Moreover, older age and lower cognitive performance were associated with higher odds of misclassification.
CONCLUSIONS: The FAQ robustly differentiates mild from moderate dementia across diverse cohorts. A threshold of ≥18 prioritizes sensitivity, whereas ≥23 favors specificity, supporting context-dependent functional staging in clinical and research settings. Individuals with FAQ scores between 18 and 22 may benefit from more detailed clinical staging.
CITATION:
Ersin Ersözlü ; Lukas Preis ; Aykut Aktuz ; Louise Droste ; Akin Erman ; Daria Gref ; Katharina Sophie Strentz ; Julian Hellmann-Regen ; For the Alzheimer’s Disease Neuroimaging Initiative and the Frontotemporal Lobar Degeneration Neuroimaging Initiative (2025): Drawing a line: Differentiating mild from moderate dementia using the functional activities questionnaire. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100630
DISTINCT SPATIAL PATTERNS OF PERIVASCULAR SPACES ENLARGEMENT FOR MULTIPLE AND CO-EXISTING PATHOLOGIES OF COGNITIVE IMPAIRMENT
Woosik Kim, Yejin Hwang, Yelim Yang, Min Gyeong Kim, Hyemin Jang, Seung Hong Choi, Joon-Kyung Seong, Roh-Eul Yoo, Wha Jin Lee
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND: This study examines how amyloid-β and vascular pathology independently and jointly relate to regional perivascular space (PVS) burden on T2-weighted MRI.
METHODS: In 307 cognitively impaired participants retrospectively identified from the Seoul National University dementia cohort, PVS were automatically quantified in the basal ganglia (BG) and lobar white matter regions from 2D T2-weighted MRI. Amyloid-β and vascular pathology positivity were defined by [18F]Florbetaben PET and small vessel disease markers. Group differences among pathology-negative (n=36), vascular-only (n=106), amyloid-only (n=48), and mixed (n=117) subgroups, as well as amyloid–vascular interactions, were assessed using analysis of covariance and multivariable linear regression.
RESULTS: BG PVS were greater in participants with vascular burden than in pathology-negative participants (F=26.97, p<0.001; Cohen's d=1.28), independent of amyloid-β. Lobar PVS were higher in single-pathology than pathology-negative participants across the parietal, temporal, and occipital regions (F=8.25–18.04, Cohen's d=0.66–0.98, all p≤0.014), with no additional increase in the mixed group. Greater amyloid-β retention was associated with parietal, temporal, and occipital PVS in VB− participants (β [95% CI]=0.55 [0.19, 0.92], 0.69 [0.35, 1.02], 0.40 [0.16, 0.64], respectively). Among AB− participants, vascular burden was associated with BG PVS (β [95% CI]=0.65 [0.40, 0.89]). Multivariable regression demonstrated less-than-additive AB×VB interactions in parietal, temporal, and occipital PVS (β [95% CI]=−0.65 [−1.08, −0.23], −0.74 [−1.13, −0.35], −0.42 [−0.70, −0.14], respectively).
CONCLUSIONS: Distinct regional PVS patterns reflect spatially selective and severity-dependent glymphatic-related structural alterations associated with amyloid-β and vascular pathologies, supporting PVS as a quantitative imaging biomarker for disentangling mixed pathways of cognitive impairment.
CITATION:
Woosik Kim ; Yejin Hwang ; Yelim Yang ; Min Gyeong Kim ; Hyemin Jang ; Seung Hong Choi ; Joon-Kyung Seong ; Roh-Eul Yoo ; Wha Jin Lee (2026): Distinct spatial patterns of perivascular spaces enlargement for multiple and Co-existing pathologies of cognitive impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100631
CAN WE IDENTIFY PEOPLE WITH ALZHEIMER’S DISEASE FROM EXAMINATION OF THE EYE? A BIDIRECTIONAL MENDELIAN RANDOMIZATION (MR) STUDY
Humayun Kiser, Ashley Budu-Aggrey, Jessica N. Cooke Bailey, Ana Villaplana-Velasco, Miguel O. Bernabeu, Xiaofan Jiang, Christopher G. Owen, Jonathan L. Haines, Louis R. Pasquale, Stuart MacGregor, Xiaoyi Raymond Gao, Janey L. Wiggs, Chen Jiang, Hélène Choquet, George Davey Smith, Patrick G. Kehoe, Neil M. Davies, Aimee L. Hanson, Emma L. Anderson, Denize Atan
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND: Neurodegeneration in Alzheimer’s disease (AD) is thought to be driven by amyloid-beta and tau deposition in the cerebral vasculature and brain. As the eye is an extension of the central nervous system, this study aimed to determine which neurovascular and neuroretinal changes in the eye are caused by AD rather than associations of the disease.
METHODS: Bidirectional two-sample univariable and multivariable Mendelian randomization (MR) methods were applied. Instrumental variables were derived from genome-wide association studies (GWAS) of AD and the following ocular features: thickness measurements of central macula (MT), retinal nerve fibre layer (mRNFL), ganglion cell-inner plexiform layer (mGCIPL), outer nuclear layer (ONL), inner segment layer (IS), and outer segment (OS) from macular region OCT scans; arteriolar tortuosity (AT), venular tortuosity (VT), venular width (VW), fractal dimension (FD), vertical cup-to-disc ratio (VCDR), optic cup area (OCA), and optic disc area (ODA) derived from other imaging methods.
RESULTS: There was strong evidence that genetic liability to AD affected the retinal vasculature by specifically increasing AT (β = 0.007;95%CI=0.002,0.011;p-value=0.005) in UK Biobank participants (n=52,798). AD may influence the mRNFL (β=-0.047,95%CI=-0.119,0.023,p-value=0.18) and mGCIPL (β=-0.061;95%CI=-0.14,0.025,p-value=0.16) of the inner retina and OS layer (β = 0.044;95%CI=-0.0001,0.08;p-value=0.05) but the evidence was weak. Multivariable MR analysis showed that a causal relationship between optic disc area and AD (OR=0.76;95%CI=0.62,0.93,p-value=0.009) was probably mediated by refractive error.
CONCLUSION: Early cerebrovascular signs of AD may be detected by examination of the eye. Further investigation is required to determine the clinical utility of eye screening for dementia.
CITATION:
Humayun Kiser ; Ashley Budu-Aggrey ; Jessica N. Cooke Bailey ; Ana Villaplana-Velasco ; Miguel O. Bernabeu ; Xiaofan Jiang ; Christopher G. Owen ; Jonathan L. Haines ; Louis R. Pasquale ; Stuart MacGregor ; Xiaoyi Raymond Gao ; Janey L. Wiggs ; Chen Jiang ; Hélène Choquet ; NEIGHBORHOOD consortium, International Glaucoma Genetics Consortium, UK Biobank Eye and Vision Consortium ; George Davey Smith ; Patrick G. Kehoe ; Neil M. Davies ; Aimee L. Hanson ; Emma L. Anderson ; Denize Atan (2026): Can we identify people with Alzheimer’s disease from examination of the eye? A bidirectional Mendelian randomization (MR) study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100635
SEX DIFFERENCES IN SUBJECTIVE COGNITION AMONG MIDDLE-AGED AND OLDER HISPANIC/LATINO ADULTS: FINDINGS FROM THE HCHS/SOL AND SOL-INCA
Ariana M. Stickel, Wassim Tarraf, Sayaka Kuwayama, Ammie Xie, Rachel Membreno, Carolina L. Costa, Carlos E.E. Araujo Menendez, Zvinka Z. Zlatar, Krista M. Perreira, Haibo Zhou, Martha Daviglus, Amber Pirzada, Paola Filigrana, Bonnie E. Levin, Linda C. Gallo, Hector M. González, Sarah J. Banks
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryINTRODUCTION: Sex differences in subjective cognitive decline (SCD) exist, yet the extent to which these differences generalize to underrepresented groups is unknown. Therefore, we investigated relationships between sex and SCD among Hispanic/Latino adults.
METHOD: Participants were 5985 Hispanic/Latino adults from the Study of Latinos - Investigation of Neurocognitive Aging. We performed survey-adjusted linear regressions to test the associations between sex (male/female) with SCD and modifications by cardiovascular disease (CVD) risk, social and language acculturation. SCD was measured using the Everyday Cognition 12-item questionnaire, including executive functioning, memory, language, and visuospatial domains.
RESULT: Overall, females reported more SCD in language and visuospatial domains. This was less pronounced for 1) language SCD at lower levels of CVD risk, and 2) visuospatial SCD with higher language acculturation.
DISCUSSION: Hispanic/Latina females self-reported more cognitive decline than males, but these differences were less pronounced in the context of lower CVD risk and higher language acculturation.
CITATION:
Ariana M. Stickel ; Wassim Tarraf ; Sayaka Kuwayama ; Ammie Xie ; Rachel Membreno ; Carolina L. Costa ; Carlos E.E. Araujo Menendez ; Zvinka Z. Zlatar ; Krista M. Perreira ; Haibo Zhou ; Martha Daviglus ; Amber Pirzada ; Paola Filigrana ; Bonnie E. Levin ; Linda C. Gallo ; Hector M. González ; Sarah J. Banks (2026): Sex differences in subjective cognition among middle-aged and older Hispanic/Latino adults: Findings from the HCHS/SOL and SOL-INCA. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100637
HIPPOCAMPAL ASYMMETRY CAPTURES NON–AMYLOID-RELATED RISK OF MEMORY DECLINE AND CLINICAL PROGRESSION
Elham Ghanbarian, Babak Khorsand, Lukai Zheng, Davis C. Woodworth, Crystal M. Glover, Maria M. Corrada, S. Ahmad Sajjadi, Joshua D. Grill, Ali Ezzati, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND: Hippocampal atrophy is a key marker of Alzheimer’s disease (AD)- related neurodegeneration; however, hippocampal volume alone may not fully capture heterogeneity in cognitive decline. Left–right hippocampal asymmetry may provide complementary information, but its prognostic value for long-term cognitive decline, particularly in relation to AD pathology, remains unclear.
OBJECTIVES: To determine whether hippocampal total volume and left-right hippocampal asymmetry provide complementary and independent information in capturing cognitive decline and clinical progression, and to examine their relationship to AD pathology.
DESIGN: Analysis of baseline MRI and longitudinal cognitive data over 10 years in four domains of memory, language, executive, and visuospatial function, using harmonized cognitive data from the Alzheimer’s Disease Sequencing Project – Phenotype Harmonization Consortium (ADSP-PHC).
SETTING: Participants from ADNI 1, ADNI GO, ADNI 2, and ADNI 3.
PARTICIPANTS: A total of 1,142 dementia-free participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with available baseline structural MRI, cerebrospinal fluid (CSF) amyloid-β (Aβ42) and phosphorylated tau (p-tau-181), and longitudinal cognitive follow-up.
MEASUREMENTS: Total hippocampal volume (left + right) and hemispheric asymmetry (absolute left–right volumetric difference) were modeled simultaneously. Linear mixed-effects models examined associations with baseline performance and longitudinal change across four cognitive domains. Cox proportional hazards models assessed risk of clinical progression to clinical dementia over up to 10 years of follow-up (median follow-up 4 years; median 5 visits per participant). All analyses adjusted for age, sex, education, APOE ε4 status, and CSF biomarkers, with stratification by amyloid status.
RESULTS: The study cohort included 546 women (47.8%), with a mean age of 72.54 ± 6.98 years. Smaller total hippocampal volume was consistently associated with worse baseline performance and faster decline across all four cognitive domains, even after adjustment for amyloid and tau. In contrast, greater left-right hippocampal asymmetry was selectively associated with worse performance and faster decline in memory, independent of total hippocampal volume. In amyloid-stratified analyses, total hippocampal volume showed broad associations with cognitive performance across multiple domains in both amyloid-positive and amyloid-negative participants, whereas hippocampal left-right asymmetry demonstrated selective associations with memory performance, which were observed only among amyloid-negative individuals. With respect to clinical progression to dementia, smaller total hippocampal volume was associated with a higher risk of progression in the overall cohort and within both amyloid groups. In contrast, hippocampal asymmetry was associated with progression risk only among amyloid-negative individuals (hazard ratio per SD increase = 1.31, 95% CI: 1.03–1.65).
CONCLUSIONS: Hippocampal total volume and asymmetry capture distinct aspects of neurodegeneration, with asymmetry providing additional prognostic information for memory decline and clinical progression in the absence of detectable amyloid pathology.
CITATION:
Elham Ghanbarian ; Babak Khorsand ; Lukai Zheng ; Davis C. Woodworth ; Crystal M. Glover ; Maria M. Corrada ; S. Ahmad Sajjadi ; Joshua D. Grill ; Ali Ezzati ; Alzheimer’s Disease Neuroimaging Initiative (2026): Hippocampal asymmetry captures non–amyloid-related risk of memory decline and clinical progression. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100638
GLYMPHATIC DYSFUNCTION, PLASMA NEUROFILAMENT LIGHT, AND CORTICAL FREE WATER MEDIATE COGNITIVE DECLINE IN FAMILIAL FRONTOTEMPORAL LOBAR DEGENERATION
Meiling Qiu, Li Ding, Rui Bao, Juanyu Gong, Wencai Ding, Zhiding Shao, Yongsheng Han, ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Research Consortium
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND: Familial frontotemporal lobar degeneration (f-FTLD) is the second most common form of young-onset dementia, with diverse clinical presentations, neuropathological substrates and genetic backgrounds. While evidence suggests that glymphatic dysfunction, neuroaxonal injury, and cortical microstructural alterations may jointly contribute to f-FTLD, their interrelationships across genotypes remain unclear.
OBJECTIVES: This study aims to investigate the roles of glymphatic dysfunction, cortical free water (cFW), and plasma neurofilament light (NfL) in f-FTLD and examine their relationship with cognitive decline.
DESIGN: A multimodal approach was applied, involving diffusion tensor imaging along the perivascular space (DTI-ALPS) for glymphatic function, plasma NfL measurement, and voxel-wise cortical free water mapping. Analyses comparing FTLD mutation groups and serial mediation analyses were conducted in 322 participants (C9orf72, GRN, MAPT mutation carriers, and matched controls).
SETTING: This study was conducted across multiple participating centers using standardized imaging protocols and harmonized multi-site data.
PARTICIPANTS: A total of 322 participants were included: 87 C9orf72 expansion carriers, 56 GRN mutation carriers, 58 MAPT mutation carriers, and 121 healthy controls.
INTERVENTION: No intervention was applied in this observational study. Participants underwent genetic testing, cognitive assessment, and diffusion MRI scans; plasma NfL was available for mutation carriers.
MEASUREMENTS: Glymphatic function was assessed using DTI-ALPS, plasma NfL levels were measured to reflect neuroaxonal injury, and cortical microstructure was assessed through cortical free water (cFW) mapping.
RESULTS: Significant reductions in DTI-ALPS and elevations in cFW were observed in C9orf72 and GRN mutation carriers, with strong associations to clinical cognitive decline. Plasma NfL levels were highest in GRN mutation carriers and correlated strongly with cognitive severity. Mediation analysis indicated that the pathway linking DTI-ALPS to cognition through NfL explained a substantial portion of the indirect effect, while residual direct effects suggested that additional mechanisms also contribute to cognitive decline.
CONCLUSIONS: This study identifies glymphatic dysfunction as a key factor contributing to cognitive decline in f-FTLD, with plasma NfL serving as an important partial mediator and cFW providing additional region-specific information.
CITATION:
Meiling Qiu ; Li Ding ; Rui Bao ; Juanyu Gong ; Wencai Ding ; Zhiding Shao ; Yongsheng Han ; ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Research Consortium (2026): Glymphatic dysfunction, plasma neurofilament light, and cortical free water mediate cognitive decline in familial frontotemporal lobar degeneration. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100639
STAGES OF OBJECTIVE MEMORY IMPAIRMENT (SOMI) AS A PREDICTOR OF CLINICAL PROGRESSION IN THE A4 STUDY
Priyanka Kumari, Richard B. Lipton, Andrew J. Aschenbrenner, Reisa Sperling, Michael C. Donohue, Ellen Grober
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND: About one third of amyloid positive, cognitively normal individuals develop mild cognitive impairment or clinical Alzheimer dementia (AD) over 5 years of follow-up. Sensitive cognitive measures, in addition to biomarkers of amyloid pathology, add to the efficiency of secondary prevention trials by identifying cognitively normal individuals at greatest risk of clinical progression. The Stages of Objective Memory Impairment (SOMI) system, based on the picture version of the Free and Cued Selective Reminding Test with immediate recall (pFCSRT+IR), predicted clinical progression in two observational studies.
OBJECTIVE: Our objective was to extend SOMI’s findings to clinical trials using participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s(A4) study.
METHODS: Eligible participants were cognitively normal, had a Clinical Dementia Rating (CDR) =0, an elevated amyloid level, the pFCSRT+IR, pTau217, and longitudinal data on the CDR. Cox proportional hazards model was used to assess the association of baseline SOMI stage for clinical progression defined by time to the first of 2 consecutive CDRs > 0 or CDR>0 at last assessment. The sample was censored at 4.5 years of follow-up.
RESULTS: Of the 911 eligible participants, mean age was 72 years, 59% were female, 62% were APOE ε4 carriers, and 37% progressed over 4.5 years. Hazard ratios (HR) for progression were estimated with follow-up time as the timescale and the SOMI 0 group as the reference. The HRs for progression across SOMI stage increased from 1.48(1.15–1.92 p=.003) for SOMI-1, to 1.83 (1.32–2.54, p ≤ 0.001) for SOMI-2, and to 3.04 (1.97–4.68, p ≤ 0.001) for SOMI 3/4. SOMI remained an independent and significant predictor when pTau217 was added to the model.
CONCLUSION: SOMI’s risk profile in A4 was similar to prior findings in observational cohorts. SOMI provides a low-cost, non-invasive enrichment tool for identifying individuals at risk for early cognitive decline in secondary prevention trials.
CITATION:
Priyanka Kumari ; Richard B. Lipton ; Andrew J. Aschenbrenner ; Reisa Sperling ; Michael C. Donohue ; Ellen Grober (2026): Stages of objective memory impairment (SOMI) as a predictor of clinical progression in the A4 study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100641
MIND GAMEPACK: A NOVEL DIGITAL HEALTH TECHNOLOGY FOR ASSESSMENT OF PARTICIPANTS WITH AND WITHOUT COGNITIVE IMPAIRMENT
Jake A. Galler, Liuqing Yang, Chao-Yi Wu, Cathrine Young, Edmarie Guzmán-Vélez, Katherine W. Cropp, Anthony W. Bannon, Hiroko H. Dodge, Jessica A. Gerber, Steven E. Arnold
J Prev Alz Dis 2026;8(13)
Show summaryHide summaryBACKGROUND: Digital biomarkers offer promising avenues for enhancing the identification, prognosis, and phenotyping of Alzheimer’s Disease (AD). This study evaluates the feasibility and utility of the MIND GamePack©, a digital game platform designed to measure leisure cognitive activity over time.
METHODS: Gameplay data were collected from 60 participants across two cohorts over 3–6 months: Cohort I (no cognitive complaints) and Cohort II (subjective complaints, mild cognitive impairment, mild dementia). Analyses focused on compliance, correlation with validated neuropsychological instruments (Montreal Cognitive Assessment [MoCA], Repeatable Battery for the Assessment of Neuropsychological Status [RBANS], and Trail Making Test [TMT]), test-retest reliability, and known groups comparison.
RESULTS: The MIND GamePack© displayed high compliance and excellent test-retest reliability within 1 week (ICC=0.81–0.95) for most selected features. Several game features displayed moderate to strong correlations with standardized neuropsychological test performance. Features related to memory tasks across select games (Normalized Accuracy and Normalized Redundant Move Variability of Memory Match and Word Repetition Rate of Word Scramble) exhibited significant associations with RBANS Sum of Index Score, TMT Part A, and MoCA, respectively. Participants without cognitive impairment exhibited improvement in features over 3 months compared to those with cognitive impairment. Baseline game features differentiated cognitively normal [CN] from cognitively impaired [CI] participants across nearly all domains after controlling for age, sex, and education (p<.01).
CONCLUSIONS: The MIND GamePack© offers a sensitive, engaging approach to cognitive monitoring and screening, with potential use for dense tracking in longitudinal research and interventional clinical trials.
CITATION:
Jake A. Galler ; Liuqing Yang ; Chao-Yi Wu ; Cathrine Young ; Edmarie Guzmán-Vélez ; Katherine W. Cropp ; Anthony W. Bannon ; Hiroko H. Dodge ; Jessica A. Gerber ; Steven E. Arnold (2026): MIND GamePack: A novel digital health technology for assessment of participants with and without cognitive impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100642
LETTER TO THE EDITOR : BEYOND RECOGNITION: REFINING THE ASSESSMENT OF PUBLIC KNOWLEDGE AND RISK PERCEPTION IN DEMENTIA PREVENTION
Zhiyan Xie, Jun Su, Tao Liao
J Prev Alz Dis 2026;8(13)
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CITATION:
Zhiyan Xie ; Jun Su ; Tao Liao (2025): Letter to the Editor: Beyond recognition: Refining the assessment of public knowledge and risk perception in dementia prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100602