Ahead of print articles
AUTOPSY FINDINGS IN ALZHEIMER\'S DISEASE CLINICAL TRIAL PARTICIPANTS DEMONSTRATE A HIGH FREQUENCY OF OFF-TARGET COEXISTING PATHOLOGIC FEATURES
E. Pinar Coskun, Justin Barber, Lauren Bojarski, Christopher J. McLouth, Erin L. Abner, Linda J. Van Eldik, Peter T. Nelson, Gregory A. Jicha
Show summaryHide summary
BACKGROUND: Having multiple comorbid neuropathologic features may confound the results of interventional trials that were designed to target a specific pathophysiologic mechanism in Alzheimer’s disease (AD) and or related dementias (ADRD). However, it is unknown what percentage of individuals undergoing AD/ADRD interventional studies have mixed pathologies.
OBJECTIVE: To characterize the spectrum of coexisting neuropathologies in brains of AD/ADRD clinical trial participants to inform trial design and therapeutic strategies
METHODS: Autopsied participants from the University of Kentucky Alzheimer Disease Research Center (UK-ADRC) community-based cohort who died between January 2005, and February 2024 were included and queried retrospectively for participation in therapeutic interventional trials. Of a total of 614 autopsied cases, 67had been enrolled in one of the following types of clinical trials: cognitively normal participants in prevention trials for AD/ADRD (designated group P; n = 21); interventions for mild cognitive impairment or early dementia (MCI/D; n = 26); and, interventions for vascular cognitive impairment (V; n = 20). The trial-engaged groups were compared to the trial-naïve group in terms of their demographic, clinical, and genetic characteristics. Pathological features (amyloid-β, tau, α-synuclein, TDP-43, and cerebrovascular disease) were assessed using consensus-based neuropathologic methods.
RESULTS: All interventions were designed to target only a single pathologic feature. The trial-engaged group did not differ significantly from those who were trial-naïve with respect to demographic, genetic (APOE), or clinical characteristics, except for a marginally higher level of education among trial participants (p = 0.04). Pure on-target pathology (i.e., only one isolated pathology was found at autopsy that was the signature pathology targeted by the intervention) was only seen in 10, 23, and 29 % of the engaged participants of V, MCI/D and P trials respectively. Comorbid pathologies were common in all three groups. On average, the trial-engaged groups altogether had a mean of 2.54 pathologic features/person, whereas the MCI/D trial-engaged group had a mean of 3.2 pathologic features/person.
CONCLUSION: Multi-etiology dementia was the norm rather than the exception for AD/ADRD trial participants. Recognizing the heterogeneity of multiple pathologies in clinical trial participants may enable the development of improved inclusion/exclusion criteria, as well as the rational use of antemortem biomarkers to stratify the likelihood of mixed comorbid pathologies that may be undesirable for single-target interventional studies. Further, multitargeted treatment strategies may be required in future trials of disease-modifying agents.
CITATION:
E. Pinar Coskun ; Justin Barber ; Lauren Bojarski ; Christopher J. McLouth ; Erin L. Abner ; Linda J. Van Eldik ; Peter T. Nelson ; Gregory A. Jicha: Autopsy findings in Alzheimer's disease clinical trial participants demonstrate a high frequency of off-target coexisting pathologic features. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.1016/j.tjpad.2026.100669
CHARACTERIZATION OF A METABOLOMICS SIGNATURE OF THE BRAIN-HEALTH-PROMOTING MIND DIET IN OLDER PERSONS
Jeanne Neuffer, Raúl González-Domínguez, Sophie Lefèvre-Arbogast, Dorrain Y Low, Alba Tor-Roca, Catherine Helmer, Andrea Du Preez, Chiara de Lucia, Silvie R. Ruigrok, Barbara Altendorfer, Ludwig Aigner, Paul J Lucassen, Aniko Korosi, Sandrine Thuret, Claudine Manach, Mercè Pallàs, Alex Sánchez-Pla, Cristina Andres-Lacueva, Mireia Urpi-Sarda, Cécilia Samieri
Show summaryHide summary
BACKGROUND: The MIND diet supports healthy cognitive aging. Yet, a challenge remains to identify individuals who do not adhere to the MIND and could be at risk for accelerated cognitive decline. A multi-metabolite biomarker panel could facilitate population screening.
OBJECTIVES: To determine and validate a blood metabolomics signature of MIND adherence in a large cohort of older adults, and to estimate its association with subsequent cognitive decline.
DESIGN, SETTING AND PARTICIPANTS: Participants were older adults (≥65 years) from the population-based three-City (3C) cohort, free of dementia at study baseline and followed for up to 12 years for cognition, who were included in two case-control samples on cognitive decline nested within two centers (Bordeaux and Dijon cities, n = 838).
EXPOSURES: 155 diet-related serum metabolites measured with a multianalyte metabolomics platform.
MAIN OUTCOMES AND MEASUREMENTS: The primary outcome was adherence to the MIND diet, assessed in a subsample of 344 participants from Bordeaux center (which underwent the dietary surveys, 24 h recall and food-frequency questionnaire). A metabolomics signature of MIND diet adherence was characterized with penalized regression and a metabolomics score (“metaboscore”) reflecting the overall MIND biological fingerprint was calculated. The secondary outcome was cognitive decline status (coded as binary: accelerated, vs. null or minimal decline) over follow-up, assessed using repeated cognitive measures in the two case-control samples. The metaboscore was reconstructed and linked to the odds of cognitive decline.
RESULTS: Eight metabolites were identified: three were associated with higher MIND adherence (3-hydroxyhippuric acid, 5-hydroxyindole-3-acetic acid, betaine - phenolic acids and amino acid related to plant foods) and five with lower MIND adherence (1-methylhistidine from red meat; cyclo(L-leucyl-L-prolyl) from coffee; tartaric acid from wine; myristoyl-carnitine and dehydroepiandrosterone sulfate, endogenous). The French-MIND metaboscore was linked to lower odds of cognitive decline, although replication was not statistically significant after multivariable adjustment.
CONCLUSION: A novel metabolomic signature of the MIND diet was characterized, which may help screen older adults at risk of poor brain nutrition and could support personalized dietary prevention strategies.
CITATION:
Jeanne Neuffer ; Raúl González-Domínguez ; Sophie Lefèvre-Arbogast ; Dorrain Y Low ; Alba Tor-Roca ; Catherine Helmer ; Andrea Du Preez ; Chiara de Lucia ; Silvie R. Ruigrok ; Barbara Altendorfer ; Ludwig Aigner ; Paul J Lucassen ; Aniko Korosi ; Sandrine Thuret ; Claudine Manach ; Mercè Pallàs ; Alex Sánchez-Pla ; Cristina Andres-Lacueva ; Mireia Urpi-Sarda ; Cécilia Samieri ; Show more: Characterization of a metabolomics signature of the brain-health-promoting MIND diet in older persons. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.1016/j.tjpad.2026.100670
PREVALENCE, RISK FACTORS, AND RACIAL DISPARITIES IN PROBABLE AND POSSIBLE DEMENTIA: THE NATIONAL HEALTH AND AGING TRENDS STUDY
Young-Shin Lee, Juan A. Cruz, Michelle Kabakibi, Alison Moore, Jung-Ah Lee, Hee-Jin Jun
Show summaryHide summary
BaACKGROUND: While global frameworks highlight modifiable risk factors for cognitive decline, evidence on how these risks affect diverse populations remains limited. This study determines the prevalence of probable and possible dementia, identifies primary predictors, and investigates risk variations across racial and ethnic groups in a nationally representative sample.
METHODS: Using a sample of 7,574 older adults from the 2023 National Health and Aging Trends Study (NHATS), cognitive status was classified as probable, possible, or no dementia. Survey-weighted multinomial logistic regression models with interaction terms examined conditional effects of age, health conditions, and sensory corrections across demographics.
RESULTS: Advanced age, low education, stroke, falls, and depression/anxiety were associated with higher Odds of possible and probable dementia (Prb-D), while female, vision and hearing aid use lowered Prb-D odds. Hispanic adults aged 85 and older faced a 60.2% predicted probability of Prb-D, compared to 35.1% for Non-Hispanic (NH) White adults. Low education disproportionately increased Prb-D prevalence, especially among Hispanics. Among hearing aid users, NH White and NH Black adults showed lower of Prb-D probability than non-users, whereas Hispanic users showed a higher probability. Chewing or swallowing problems severely escalated Prb-D probability for Hispanic adults (42.2%) compared to NH Whites (19.3%), and depression doubled the overall risk of Prb-D.
CONCLUSION: The burden of cognitive decline is deeply unequal, proving standardized interventions insufficient for minority older adults. Addressing these disparities necessitates culturally responsive care pathways and the elimination of structural barriers, particularly inadequate insurance coverage for audiology and dental services.
CITATION:
Young-Shin Lee ; Juan A. Cruz ; Michelle Kabakibi ; Alison Moore ; Jung-Ah Lee ; Hee-Jin Jun: Prevalence, risk factors, and racial disparities in probable and possible dementia: the national health and aging trends study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.1016/j.tjpad.2026.100676
EDITORIAL: WHAT\'S GOOD FOR THE HEART IS GOOD FOR THE BRAIN? EVIDENCE FROM A RURAL COHORT ON THE LONGITUDINAL RELATIONSHIP BETWEEN ATHEROSCLEROTIC CARDIOVASCULAR DISEASE RISK AND COGNITIVE DECLINE
Maileen G. Ulep
Show summaryHide summary
CITATION:
Maileen G. Ulep: Editorial: What's good for the heart is good for the brain? Evidence from a rural cohort on the longitudinal relationship between atherosclerotic cardiovascular disease risk and cognitive decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.1016/j.tjpad.2026.100672
CORRIGENDUM TO “REAL-WORLD LONG-TERM CONTINUATION OF LECANEMAB THERAPY AND THE CLINICAL UTILITY OF PHOSPHORYLATED TAU 181” [THE JOURNAL OF PREVENTION OF ALZHEIMER\'S DISEASE (2026) 100664]
Moeko Noguchi-Shinohara, Daiki Muramatsu, Ayano Shima, Yasuhiro Sakashita, Yasutake Tada, Hiroki Yamaguchi, Junji Komatsu, Tokuhei Ikeda, Kenjiro Ono
Show summaryHide summary
CITATION:
Moeko Noguchi-Shinohara ; Daiki Muramatsu ; Ayano Shima ; Yasuhiro Sakashita ; Yasutake Tada ; Hiroki Yamaguchi ; Junji Komatsu ; Tokuhei Ikeda ; Kenjiro Ono: Corrigendum to “Real-world long-term continuation of lecanemab therapy and the clinical utility of phosphorylated tau 181” [The Journal of Prevention of Alzheimer's Disease (2026) 100664]. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.1016/j.tjpad.2026.100668
EDITORIAL: OPPORTUNITIES TO TREAT SPECIFIC POPULATIONS WITH REPURPOSED DRUGS
Serge Gauthier
Show summaryHide summary
CITATION:
Serge Gauthier: Editorial: Opportunities to treat specific populations with repurposed drugs. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.1016/j.tjpad.2026.100671
EDITORIAL: FROM ADVICE TO AGENCY: MAKING BRAIN HEALTH ACTIONABLE AND EQUITABLE FOR MIDDLE-AGED ADULTS WITH MILD NEUROCOGNITIVE DISORDER
Hermine Lenoir
Show summaryHide summary
CITATION:
Hermine Lenoir: Editorial: From advice to agency: making brain health actionable and equitable for middle-aged adults with mild neurocognitive disorder. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.1016/j.tjpad.2026.100667
INTEGRATING FRAILTY INTO DECISION-MAKING FOR DISEASE-MODIFYING THERAPIES IN ALZHEIMER’S DISEASE: A PROPOSED EXPERT-OPINION BASED APPROACH
Giuseppe Bellelli, Ovidio Brignoli, Marco Canevelli, Antonio Cherubini, Maria Cristina Ferrara, Laura Fratiglioni, Giovanni B. Frisoni, Giulia Grande, Alberto Magni, Martina Marelli, Alessandra Marengoni, Nicolás Martínez Velilla, Marc Suárez-Calvet, Suzanne Timmons, Alessandro Padovani
Show summaryHide summary
The introduction of disease-modifying therapies for Alzheimer’s disease (AD-DMTs) is reshaping clinical practice, raising critical questions about patient selection, diagnostic pathways, treatment appropriateness, and equity of access. Frailty, a multidimensional condition of reduced physiological reserve and increased vulnerability to stressors, is common in older adults with AD, yet has not been systematically assessed in AD-DMTs trials, limiting the generalizability of trial findings to real-world populations.
In this review, we examine the role of frailty in the emerging era of AD-DMTs, summarizing evidence on its prevalence and prognostic relevance, approaches to its assessment, and its potential impact on treatment safety and effectiveness. We propose that regular frailty assessment should inform decision-making in both clinical trials and clinical practice, while frailty-informed management—including medication review and multidomain interventions—may support more appropriate, individualized care.
CITATION:
Giuseppe Bellelli ; Ovidio Brignoli ; Marco Canevelli ; Antonio Cherubini ; Andrew Clegg ; Bruno Dubois ; Maria Cristina Ferrara ; Laura Fratiglioni ; Giovanni B. Frisoni ; Giulia Grande ; Frank Jessen ; Sean P Kennelly ; Alberto Magni ; Martina Marelli ; Alessandra Marengoni ; Nicolás Martínez Velilla ; Susan D. Shenkin ; Marc Suárez-Calvet ; Suzanne Timmons ; Alessandro Padovani: Integrating frailty into decision-making for disease-modifying therapies in Alzheimer’s disease: a proposed expert-opinion based approach. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.1016/j.tjpad.2026.100666
REAL-WORLD LONG-TERM CONTINUATION OF LECANEMAB THERAPY AND THE CLINICAL UTILITY OF PHOSPHORYLATED TAU 181
Moeko Noguchi-Shinohara, Daiki Muramatsu, Ayano Shima, Yasuhiro Sakashita, Junji Komatsu, Tokuhei Ikeda, Kenjiro Ono
Show summaryHide summary
This real-world study evaluated the long-term feasibility of lecanemab treatment in 117 patients with early Alzheimer's disease at Kanazawa University Hospital. To assess treatment persistence over a full 18-month course, we focused on the 64 patients who initiated treatment between January and December 2024. Of these 64 patients, 78.1% completed the full 18-month course, and all 48 eligible patients elected to continue beyond 18 months. The overall discontinuation rate was 21.9%, with amyloid-related imaging abnormalities (ARIA) (27.7%), decreased motivation (22.2%), and cognitive decline (11.1%) as the primary reasons. Among all 117 patients, ARIA occurred in 12.9% and was significantly associated with apolipoprotein Eε4 carrier status, elevated baseline cerebrospinal fluid (CSF)-phosphorylated tau (ptau) 181 (ptau181; ≥78.6 pg/ml), ≥2 microbleeds, and Fazekas score≥2 deep white matter hyperintensity. Elevated CSF-ptau181 also independently predicted cognitive decline during treatment and ARIA-related discontinuation. These findings suggest that integrating CSF-ptau181 measurement and baseline MRI into clinical decision-making may support individualized risk stratification and the safe, sustained use of lecanemab in real-world practice.
CITATION:
Moeko Noguchi-Shinohara ; Daiki Muramatsu ; Ayano Shima ; Yasuhiro Sakashita ; Yasutake Tada ; Hiroki Yamaguchi ; Junji Komatsu ; Tokuhei Ikeda ; Kenjiro Ono ; ; (): Real-world long-term continuation of lecanemab therapy and the clinical utility of phosphorylated tau 181. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.1016/j.tjpad.2026.100664
LETTER TO THE EDITOR : RESPONSE TO TWO LETTERS ON OMEGA-3 SUPPLEMENTATION AND COGNITIVE DECLINE
Zheng-Bin Liao, Ye-Ran Wang
Show summaryHide summary
CITATION:
Zheng-Bin Liao ; Ye-Ran Wang: Letter to the Editor: Response to two letters on omega-3 supplementation and cognitive decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100662
LETTER TO THE EDITOR : OXIDATION OVER OMEGA-3: REINTERPRETING THE PARADOXICAL LINK BETWEEN FISH OIL SUPPLEMENTS AND ACCELERATED COGNITIVE DECLINE
Dong\'e Huang, Munan Lin, Junqing Dong
Show summaryHide summary
CITATION:
Dong'e Huang ; Munan Lin ; Junqing Dong (2026): Letter to the Editor: Oxidation over omega-3: Reinterpreting the paradoxical link between fish oil supplements and accelerated cognitive decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100660
LETTER TO THE EDITOR : DO METHODOLOGICAL LIMITATIONS AND CONFOUNDING FACTORS EXPLAIN THE APPARENT ACCELERATION OF COGNITIVE DECLINE IN OLDER ADULTS TAKING OMEGA-3 FATTY ACID SUPPLEMENTS?
Simon C. Dyall, Mélanie Plourde
Show summaryHide summary
CITATION:
Simon C. Dyall ; Mélanie Plourde (2026): Letter to the Editor: Do methodological limitations and confounding factors explain the apparent acceleration of cognitive decline in older adults taking omega-3 fatty acid supplements?. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100661
NATIONAL PREVALENCE AND CARE NEEDS OF DEMENTIA IN ADULTS AGED >=55 YEARS: FINDINGS FROM THE CHINA MENTAL HEALTH SURVEY
Zhaorui Liu, Guangming Xu, Ruoxi Ding, Chao Ma, Yueqin Huang, Lingjiang Li, Tingting Zhang, Jie Yan, Yaqin Yu, Xiufeng Xu, Zhizhong Wang, Yifeng Xu, Tao Li, Huifang Yin, Xiangdong Xu, Limin Wang, Yongping Yan, Shuiyuan Xiao
Show summaryHide summary
BACKGROUND: Dementia is a major global mortality cause and key driver of disability in older adults, imposing multidimensional burdens. As China's population ages, accurate prevalence estimates and care need assessments are essential for equitable policy planning. This study investigates young- and late-onset dementia prevalence while comparing health service utilization and unmet care needs between affected and unaffected populations.
METHODS: Utilizing China Mental Health Survey data (2013-2015) with multistage probability sampling, we identified 12,663 nationally representative adults aged ≥55 years. Of these, 10,839 completed Stage I assessments and 2,261 received Stage II evaluations, supplemented by psychiatric assessments of initial non-participants (n=197). Dementia diagnosis followed DSM-IV criteria via validated cognitive/functional instruments. Health service utilization and multidimensional care needs (ADLs/IADLs/safety) were quantified through participant/informant interviews.
RESULTS: Among 2 458 participants assessed, dementia prevalence was 2.65% (55-64y) and 5.56% (≥65y). Rural residents showed consistently higher rates than urban counterparts across age groups. Significant education gradients emerged, with urban prevalence decreasing with higher education while rural patterns differed. Individual living with dementia required substantially more care for both samples (55-64 years: 37.4% vs 11..9%, +81.3 monthly hours; 65+ years: 62.6% vs 13.4%, +88.8 monthly hours) without increased health service utilization.
CONCLUSION: This national study reveals substantial dementia burden in China, exposing systemic healthcare deficiencies through misaligned functional care needs and medical engagement. The neglect of chronic disability management in aging populations necessitates urgent integration of prevention strategies and tailored support frameworks within primary care systems.
CITATION:
Zhaorui Liu ; Guangming Xu ; Ruoxi Ding ; Chao Ma ; Yueqin Huang ; Lingjiang Li ; Tingting Zhang ; Jie Yan ; Yaqin Yu ; Xiufeng Xu ; Zhizhong Wang ; Yifeng Xu ; Tao Li ; Huifang Yin ; Xiangdong Xu ; Limin Wang ; Yongping Yan ; Shuiyuan Xiao (2026): National Prevalence and Care Needs of Dementia in Adults Aged >=55 Years: Findings from the China Mental Health Survey. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100659
PREVALENCE OF DEMENTIA AND BPSD IN COMMUNITY-DWELLING OLDER ADULTS WITH ADVANCED CARE NEEDS: A NATIONWIDE SURVEY IN TAIWAN
Kai-Ming Jhang, Yu-Chun Tung, Wen-Fu Wang, Hsiang-Ju Chung, Hui-Yi Liao, Ling-Chun Huang, Chih-Cheng Hsu, Yuan-Han Yang
Show summaryHide summary
BACKGROUND: Caring for people with both dementia and advanced care needs is complex. This study aimed to elucidate the prevalence of dementia and behavioral and psychological symptoms of dementia (BPSD) in patients receiving advanced care, including tube feeding, respiratory care, subcutaneous injection, urinary catheter, stoma care or enema, wound care, pain care, or dialysis.
METHODS: This study was a nationwide, population-based, cross-sectional survey. A total of 11,297 participants were enrolled between September 2020 and June 2022 using a multistage stratified systematic sampling design. Dementia diagnosis was made by subspecialists during in-home visit or by expert consensus. The presence of BPSD and the use of specific advanced care services were collected by trained interviewers.
RESULTS: Overall, 732 (6.5%) participants received at least one item of advanced care and 975 (8.6%) were diagnosed with dementia. Participants receiving advanced care had a higher prevalence of dementia (18.0%vs. 8.0%, p < 0.0001). Subjects receiving stoma or enema care (OR=4.92, 95% CI=2.29–10.59, p < 0.0001), tube feeding (OR=3.20, 95%CI=1.99–5.15, p < 0.0001), dialysis (OR=2.97, 95% CI=1.80–4.92, p < 0.0001), urinary catheterization or intermittent catheterization (OR=2.20, 95% CI=1.32–3.67, p = 0.003), and respiratory care (OR=2.01, 95% CI=1.14–3.57, p = 0.017) had a significantly higher risk of dementia. For BPSD, day–night confusion (42.0%vs. 27.9%, p = 0.002) and care-resistant behaviors (19.8%vs. 12.0%, p = 0.019) were significantly more prevalent in participants receiving advanced care.
CONCLUSIONS: This study found that patients receiving advanced care had a significantly higher prevalence of dementia and BPSD in Taiwanese population. Healthcare professionals should be vigilant regarding potential comorbid dementia in patients receiving advanced care and provide more patient-centered approaches or non-pharmacological interventions to alleviate BPSD and reduce care partner’s loading.
CITATION:
Kai-Ming Jhang ; Yu-Chun Tung ; Wen-Fu Wang ; Hsiang-Ju Chung ; Hui-Yi Liao ; Ling-Chun Huang ; Chih-Cheng Hsu ; Yuan-Han Yang (2026): Prevalence of dementia and BPSD in community-dwelling older adults with advanced care needs: a nationwide survey in Taiwan. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100656
PREDICTIVE VALUE OF THE ALZHEIMER POLYGENIC RISK SCORE ON COGNITIVE DECLINE IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT AND ALZHEIMER\'S DISEASE DEMENTIA
Berta Calm, Adrián Hinojosa-Calleja, Fernando García-Gutiérrez, Josep Blazquez-Folch, Montserrat Alegret, Maria Victoria Fernández, Itziar De Rojas, Pablo García-González, Clàudia Olivé, Alejandro Valenzuela-Seba, Paula Bayón-Buján, Amanda Cano, Raquel Puerta, Maria Capdevila-Bayo, Álvaro Muñoz-Morales, Andrea Miguel, Ariadna Solivar, Laura Montrreal, Pilar Sanz-Cartagena, Maitee Rosende-Roca, Yahveth Cantero-Fortiz, Miren Jone Gurruchaga, Lluís Tárraga, Mercè Boada, Marta Marquié, Agustín Ruiz, Sergi Valero, for theAlzheimer’s Disease Neuroimaging Initiative
Show summaryHide summary
BACKGROUND: Polygenic risk scores for Alzheimer’s disease (AD-PRS) are widely used to estimate genetic susceptibility to AD, but their relationship with the rate of cognitive decline (CD) after clinical onset remains insufficiently characterized.
OBJECTIVES: To examine the association between AD-PRS and longitudinal CD across the AD spectrum and to evaluate the predictive contribution of individual AD-PRS variants.
DESIGN: Large longitudinal observational study in a single-center cohort, with an external cohort to assess generalizability.
SETTING: Memory clinic cohort from Ace Alzheimer Center Barcelona (Ace) with external cohort using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
PARTICIPANTS: The study included 7,233 patients from Ace and 863 from ADNI, with a mean follow-up of 5.4 years in Ace and 3.6 years in ADNI. A biomarker sub-cohort included 1075 participants from Ace and 569 from ADNI.
MEASUREMENTS: CD was quantified as the annual change in Mini-Mental State Examination (MMSE) scores estimated using linear mixed-effects models. Associations between AD-PRS and longitudinal MMSE trajectories were tested adjusting for clinical and sociodemographic (CSD) variables and APOE genotype. Machine learning models and SHapley Additive exPlanations (SHAP) were used to evaluate the predictive relevance of individual variants.
RESULTS: Higher AD-PRS was associated with faster CD in the full clinical cohort and in biomarker subset, independently of APOE genotype. AD-PRS was not associated with baseline MMSE. APOE ε4 was associated with lower baseline MMSE and faster CD only in the full clinical sample. Genetic predictors provided limited improvement beyond CSD variables, and model performance showed limited reproducibility across cohorts.
CONCLUSIONS: AD-PRS is associated with longitudinal CD across the AD spectrum. Although polygenic burden contributes to variability in cognitive trajectories, its added predictive value beyond routinely available clinical variables remains modest.
CITATION:
Berta Calm ; Adrián Hinojosa-Calleja ; Fernando García-Gutiérrez ; Josep Blazquez-Folch ; Montserrat Alegret ; Maria Victoria Fernández ; Itziar De Rojas ; Pablo García-González ; Clàudia Olivé ; Alejandro Valenzuela-Seba ; Paula Bayón-Buján ; Amanda Cano ; Raquel Puerta ; Maria Capdevila-Bayo ; Álvaro Muñoz-Morales ; Andrea Miguel ; Ariadna Solivar ; Laura Montrreal ; Pilar Sanz-Cartagena ; Maitee Rosende-Roca ; Yahveth Cantero-Fortiz ; Miren Jone Gurruchaga ; Lluís Tárraga ; Mercè Boada ; Marta Marquié ; Agustín Ruiz ; Sergi Valero ; for theAlzheimer’s Disease Neuroimaging Initiative (2026): Predictive value of the Alzheimer polygenic risk score on cognitive decline in patients with mild cognitive impairment and Alzheimer's disease dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100658
BRAIN HEALTH STRATEGIES IN MIDDLE-AGED INDIVIDUALS WITH MILD NEUROCOGNITIVE DISORDER: A SCOPING REVIEW
Joshi Dookhy, Yvonne McCague, Jim Hickson, Diarmuid Stokes, Thilo Kroll, Kate Frazer
Show summaryHide summary
Brain health refers to optimal brain functioning and integrity, shaped by complex cognitive, psychological, and social determinants. Individuals with mild neurocognitive disorder (mNCD) are at higher risk of developing dementia. Prioritising brain health is essential throughout the lifespan, particularly at midlife when health risks often emerge alongside heavy life responsibilities. International frameworks emphasise addressing modifiable risk factors across the lifespan to reduce dementia risk, yet little is known about the strategies middle-aged individuals with mNCD use to maintain brain health in everyday life. Understanding how people in midlife interpret and act on information about brain health is essential to align clinical care and prevention policies with lived experience. This scoping review followed the Joanna Briggs Institute methodology and mapped data published from August 2015 to 2025 using the 2024 Lancet Commission on dementia and the Cochrane PROGRESS-Plus equity framework. The primary aim of this review was to map the range and characteristics of non-pharmacological brain health strategies used by middle-aged individuals with mNCD to reduce the risks of developing dementia. After screening 6349 records, 17 articles were included. The results are presented in three groups: brain health strategies, facilitators and barriers across strategies, and the equity analysis. Strategies were classified as formalised interventions and self-directed practices. Facilitators and barriers varied according to population characteristics and the strategies used. Equity gaps included limited representation of study participants from rural and low-socioeconomic settings, reduced generalisability to male populations, and underrepresentation of minoritised ethnic groups. Clinicians, service planners, and policymakers should prioritise equity-oriented brain health strategies co-designed with middle-aged individuals. Equity and co-design should be explicitly integrated within global brain health policies and agendas.
CITATION:
Joshi Dookhy ; Yvonne McCague ; Jim Hickson ; Diarmuid Stokes ; Thilo Kroll ; Kate Frazer (2026): Brain health strategies in middle-aged individuals with mild neurocognitive disorder: a scoping review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100657
LETTER TO THE EDITOR : FROM REGULATORY APPROVAL TO CLINICAL PRACTICE: REAL-WORLD ELIGIBILITY FOR ANTI-AMYLOID MONOCLONAL ANTIBODIES IN AN ITALIAN DEMENTIA-CARE NETWORK
Giovanna Zamboni, Manuela Tondelli, Giulia Vinceti, Chiara Gallingani, Zeno Bercini, Aurora Barbieri, Chiara Carbone, Najara Iacovino, Silvia Cossutti, Daniela Ballotta, Simone Salemme, Annalisa Chiari
Show summaryHide summary
CITATION:
Giovanna Zamboni ; Manuela Tondelli ; Giulia Vinceti ; Chiara Gallingani ; Zeno Bercini ; Aurora Barbieri ; Chiara Carbone ; Najara Iacovino ; Silvia Cossutti ; Daniela Ballotta ; Simone Salemme ; Annalisa Chiari (2026): Letter to the Editor: From regulatory approval to clinical practice: real-world eligibility for anti-amyloid monoclonal antibodies in an Italian dementia-care network. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100655
THE MISSING IMPROVERS: TAU PATHOLOGY, NEUROPLASTICITY, AND THE CASE FOR TAU-INFORMED PATIENT SELECTION BEFORE AMYLOID IMMUNOTHERAPY
Eric Dinnerstein
Show summaryHide summary
Amyloid immunotherapy with lecanemab and donanemab has been approved on the basis of statistically significant slowing of cognitive and functional decline in early Alzheimer's disease (1,2). Yet clinicians treating individual patients face the everyday challenge of estimating whether a given patient is declining at the rate that would be expected for them, and whether their trajectory reflects a response to treatment. I argue that this difficulty arises in large part because the field cannot yet routinely stratify patients by tau pathology before treatment, even though tau burden is among the strongest available predictors of both the rate of progression and the magnitude of response to amyloid-targeting therapy. Post-hoc and open-label analyses of the Clarity AD and TRAILBLAZER-ALZ 2 programmes suggest that patients with absent, low, or medium tau burden may constitute a biologically distinct group in whom amyloid clearance is most likely to permit clinical stabilization or measurable functional gain. These observations remain hypotheses, generated largely from subgroup, open-label, and biomarker data rather than from prospective trials designed to test them I propose that tau status should be given strong consideration in patient selection, that tau-guided selection should be evaluated prospectively, and that the access, reimbursement, and standardization barriers to tau positron emission tomography (PET) — together with the promise of scalable plasma tau biomarkers — be addressed deliberately as the field moves toward tau-informed treatment. One tau PET tracer is currently approved by the US Food and Drug Administration, and a regulatory decision on a second is anticipated in 2026.
CITATION:
Eric Dinnerstein (2026): The missing improvers: Tau pathology, neuroplasticity, and the case for tau-informed patient selection before amyloid immunotherapy. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100653
COMPREHENSIVE SOCIAL DETERMINANTS OF HEALTH AND BRAIN HEALTH IN MIDLIFE
Christina S. Dintica, Julia Cheunkarndee, R. Nick Bryan, Lenore J. Launer, Kristine Yaffe
Show summaryHide summary
BACKGROUND: Social determinants of health (SDOH) are increasingly recognized as important drivers of cognitive outcomes. However, most existing evidence focuses on individual SDOH components and older populations.
OBJECTIVES: To develop a comprehensive SDOH index and examine its association with subsequent changes in cognitive function and structural brain measures in midlife.
DESIGN: Prospective cohort study with repeated measures of cognition and brain imaging.
SETTING: Community-based cohort from the Coronary Artery Risk Development in Young Adults (CARDIA) study.
PARTICIPANTS: A total of 3488 participants with SDOH data in early midlife (mean age 40.0 ± 3.6 years); 645 participants had repeated brain magnetic resonance imaging (MRI) data.
MEASUREMENTS: A weighted aggregate SDOH index was constructed from 12 items across 5 domains: economic stability, community and social context, education, neighborhood and built environment, and health care access. Cognitive function was assessed using the Digit Symbol Substitution Test (DSST), Stroop Test, and Rey Auditory Verbal Learning Test (RAVLT). Brain MRI outcomes included white matter hyperintensities (WMHs) and total gray matter (GM) volume. Mixed linear regression models examined associations between SDOH quartiles and longitudinal cognitive and MRI outcomes, adjusting for demographics, vascular risk factors, depression, and intracranial volume (for MRI).
RESULTS: At baseline, participants in the most disadvantaged SDOH quartile performed worse across all cognitive tests compared with the least disadvantaged quartile (p < 0.001). Over time, the most disadvantaged quartile showed steeper decline in DSST performance (adj. mean change: −0.72, 95% CI: −0.93 to −0.52 vs. −0.55, 95% CI: −0.76 to −0.34, p = 0.013), greater WMH accumulation (ratio: 1.07, 95% CI: 1.05 to 1.09 vs. 1.04, 95% CI: 1.03 to 1.05, p = 0.007), and steeper decline in total GM volume (−2.02 cm³, 95% CI: −2.39 to −1.65 vs. −1.46 cm³, 95% CI: −1.71 to −1.20, p = 0.011) per 5-year interval compared to the least disadvantaged quartile.
CONCLUSIONS: Greater social disadvantage in midlife is associated with worse baseline cognition and accelerated decline in cognitive function and brain integrity. These findings highlight the importance of SDOH as key determinants of brain health in midlife and suggest that strategies to mitigate social disadvantage may help preserve cognitive and brain health.
CITATION:
Christina S. Dintica ; Julia Cheunkarndee ; R. Nick Bryan ; Lenore J. Launer ; Kristine Yaffe (2026): Comprehensive social determinants of health and brain health in midlife. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100652
CHOROID PLEXUS VOLUME IN PATHOLOGY-CONFIRMED ALZHEIMER\'S DISEASE
Francis Fernandes, Avyarthana Dey, Andy Ma, Nathan W. Churchill, Corinne E. Fischer, Simon J. Graham, David G. Munoz, Tom A. Schweizer
Show summaryHide summary
INTRODUCTION: The choroid plexus (CP) increases in volume across the Alzheimer’s disease (AD) continuum, suggesting its potential as a clearance-related biomarker. However, few studies have examined ante-mortem CP volume in relation to post-mortem AD pathology, the gold standard for diagnosis.
METHODS: Participants who had structural magnetic resonance imaging and post-mortem pathology, with an interval of ≤ 5 years between imaging and death, were examined. Normalized CP volume (NCPV) was semi-automatically segmented from the lateral ventricles and analyzed using Bayesian linear regression to estimate associations with cognitive impairment (CI), AD pathology, and relevant clinical/demographic data.
RESULTS: Intermediate and high levels of AD pathology and CI were associated with larger NCPV, whereas female sex was associated with lower NCPV. Subgroup analyses showed larger NCPV in individuals with greater CI despite comparable levels of AD pathology.
DISCUSSION: These findings link CP enlargement to neuropathologically confirmed AD burden and CI, supporting further investigation of CP structure and function in AD.
CITATION:
Francis Fernandes ; Avyarthana Dey ; Andy Ma ; Nathan W. Churchill ; Corinne E. Fischer ; Simon J. Graham ; David G. Munoz ; Tom A. Schweizer (2026): Choroid plexus volume in pathology-confirmed Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100648
RISK OF DEMENTIA AFTER INITIATION OF GLP-1 RA VERSUS LONG-ACTING INSULIN IN PATIENTS WITH TYPE 2 DIABETES MELLITUS
Chien-Hung Lin, Peir-Haur Hung, Mu-Chi Chung, Laing-You Wu, Chi-Jung Chung
Show summaryHide summary
BACKGROUND: Recent studies suggest a decreased risk of dementia in patients treated with glucagon-like peptide-1 receptor agonist (GLP-1 RA). In this study, we compare the risk of dementia associated with GLP-1 RA versus long-acting insulin in adults aged over 50 years with type 2 diabetes (T2DM) using real-world administrative data from a large Taiwan cohort
DESIGN: A population-based retrospective cohort study
SETTING: We analyzed 10,783 propensity score-matched pairs of adults with T2DM who initiated either GLP-1 RA or long-acting insulin from Taiwan's National Health Insurance Research Database (2011-2021).
MEASUREMENTS: Primary outcome was new-onset dementia; secondary outcomes included dementia requiring treatment and specific dementia subtypes (Alzheimer's disease, vascular dementia, and unspecified dementia). Hazard ratios (HRs) were estimated using Cox models. Results: Analysis of matched pairs identified 375 cases of newly diagnosed dementia. The incidence rate was 4.86 per 1,000 person-years in GLP-1 RA users versus 7.56 in insulin users. GLP-1 RA use was associated with significantly lower risk of overall dementia (HR 0.64, 95% CI 0.46-0.89, P=0.0072) and unspecified dementia (HR 0.41, 95% CI 0.24-0.68, P=0.0006), but not for Alzheimer's disease (HR 1.48, 95% CI 0.61-3.63, P=0.3867) or vascular dementia (HR 1.66, 95% CI 0.21-13.03, P=0.6324). Among GLP-1 RAs, both liraglutide (HR 0.40, 95% CI 0.20-0.80, P=0.0091) and dulaglutide (HR 0.42, 95% CI 0.19-0.92, P=0.0311) showed significant protective effects against unspecified dementia.
CONCLUSIONS: GLP-1 RA use was associated with lower dementia risk versus long-acting insulin in T2DM patients, especially with liraglutide and dulaglutide. As observational, causality requires confirmation from randomized controlled trials.
CITATION:
Chien-Hung Lin ; Peir-Haur Hung ; Mu-Chi Chung ; Laing-You Wu ; Chi-Jung Chung (2026): Risk of Dementia after initiation of GLP-1 RA versus long-acting insulin in patients with type 2 Diabetes mellitus. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100645
QUANTIFYING GENERALIZATION ERROR IN MACHINE LEARNING PREDICTION OF COGNITIVE DECLINE
Roya Melanie Hüppi, Nicolas Langer, Bruno Hebling Vieira, for the Alzheimer’s Disease Neuroimaging Initiative
Show summaryHide summary
BACKGROUND: Predicting cognitive decline as a continuum, from healthy age-related decline to mild cognitive impairment and dementia, enables more precise individual-level predictions. However, the practical value of such models for early intervention and prevention depends on their ability to generalize to independent cohorts, a property that is often not evaluated.
OBJECTIVES: This study investigated whether adding structural magnetic resonance imaging (MRI) to non-brain data improved machine learning predictions of continuous cognitive decline and analyzed the models’ generalizability.
DESIGN: Multi-target random forest regression models predicted annual decline in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) using non-brain data, structural MRI data, or their combination from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 1237) and Open Access Series of Imaging Studies (OASIS-3; N = 662) datasets. Cross-site generalizability was evaluated.
SETTING: Data from ADNI and OASIS-3 were used for this study.
PARTICIPANTS: A total of 1899 participants who had demographic, clinical, and brain imaging data from a baseline session and clinical data from at least 2 follow-up sessions were included.
MEASUREMENTS: Baseline non-brain (demographics, clinical and neuropsychological scores, information on APOE genotype, cognitive diagnosis, health, and number of sessions before baseline) and/or structural MRI data were used to predict the yearly rate of change in CDR-SOB and MMSE scores.
RESULTS: Including structural MRI data improved prediction of CDR-SOB and MMSE change, reaching respective R2 values of .41 and .33 in ADNI and .42 and .33 in OASIS-3. Model performance for across-dataset predictions was reduced (R2 between .18 and .35), unexplained by distributional shifts of target variables. Models using only top predictive features performed similarly to full models when tested externally (R2 between .18 and .34), suggesting predictor redundancy.
CONCLUSIONS: Incorporating structural MRI data enhances within-dataset prediction of continuous cognitive decline, allowing for more precise individual-level prediction and advancing towards precision medicine. Even though external validation remains limited, quantifying the generalizability gap is a crucial step towards the responsible use of ML models in clinical intervention and prevention.
CITATION:
Roya Melanie Hüppi ; Nicolas Langer ; Bruno Hebling Vieira ; for the Alzheimer’s Disease Neuroimaging Initiative (2026): Quantifying generalization error in machine learning prediction of cognitive decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100646
COST-EFFECTIVENESS OF THE SPECIAL CARE UNIT FOR PERSONS WITH DEMENTIA
Ron Handels, Bernhard Michalowsky, Aline Mendes, Sverre Bergh, Bruno Mario Cesana, Alfonso Ciccone, Emmanuel Cognat, Andrea Fabbo, Sara Fascendini, Giovanni B. Frisoni, Lutz Froelich, Patrizia Mecocci, Paola Merlo, Oliver Peters, Magdalini Tsolaki, Carlo Alberto Defanti, RECage consortium collaborators
Show summaryHide summary
INTRODUCTION: We aimed to estimate the cost-effectiveness of the patient-centered special care unit for behavioral and psychological symptoms of dementia (SCU-B) in the Respectful Caring for the Agitated Elderly (RECage) study.
METHODS: A health-economic evaluation was performed alongside a controlled European multicenter three-year longitudinal cohort study enrolling 508 participants in a non-SCU-B cohort and SCU-B cohort. Health service resource use, costs, quality-adjusted life years (QALYs), and incremental cost per QALY gained were assessed.
RESULTS: Total QALYs were lower (−0.13; bootstrap-interval −0.23 to −0.02) and total costs were higher (€24,960; bootstrap-interval 14,870 to 35,090) in the SCU-B cohort. Base case and sensitivity analyses indicated the SCU-B was likely not cost-effective.
DISCUSSION: Widespread implementation as well as disinvestment of SCU-B cannot be recommended, given the uncertainty of the study results. We recommend a randomized study stratified by (local/county) region for conclusive evidence.
CITATION:
Ron Handels ; Bernhard Michalowsky ; Aline Mendes ; Sverre Bergh ; Bruno Mario Cesana ; Alfonso Ciccone ; Emmanuel Cognat ; Andrea Fabbo ; Sara Fascendini ; Giovanni B. Frisoni ; Lutz Froelich ; Patrizia Mecocci ; Paola Merlo ; Oliver Peters ; Magdalini Tsolaki ; Carlo Alberto Defanti ; RECage consortium collaborators (2026): Cost-effectiveness of the special care unit for persons with dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100647
TIMING OF COGNITIVE DECLINE ONSET AND LIFE-COURSE TRAJECTORIES A POOLED LONGITUDINAL ANALYSIS OF 14,389 ADULTS ACROSS THREE COHORTS
Jan Sebastian Novotný, Sivan Klil-Drori, Yonas Endale Geda, Ziad Nasreddine, Gorazd Bernard Stokin
Show summaryHide summary
BACKGROUND: Population ageing is driving a global surge in cognitive impairment. While late-life decline is well-characterized, the onset of measurable cognitive changes across the full adult lifespan remains uncertain. We aimed to estimate the age at which detectable decline begins using longitudinal data from three population-based cohorts from three countries spanning three continents.
METHODS: We analyzed participant-level longitudinal data from the China Health and Retirement Longitudinal Study (CHARLS; China), Midlife in the United States (MIDUS; USA), and Kardiovize (KV; Czech Republic). Cognitive performance was assessed using validated instruments (TICS, BTACT, and MoCA). Scores were harmonized using the percent of maximum possible method (0-100 metric). Linear mixed-effects models, adjusted for age group, sex, and education estimated change over an average 7–9-year follow-up.
FINDINGS: In pooled sample of 14,389 participants (baseline age 22-94 years), a detectable decline in total cognition first emerged in the 31-40 age group (mean change -1.2 points, 95% CI -2.1 to -0.3). Decline magnitude increased progressively with age, reaching -11.4-points in the oldest strata (all p<0.001). Non-memory domains showed earlier vulnerability (detectable from age 31), while significant memory decline emerged after age 50. Individual trajectories showed substantial heterogeneity, suggesting that chronological age is not a deterministic proxy for decline.
INTERPRETATION: Population-level cognitive decline became detectable in early midlife, decades before the traditional clinical focus on older age. Across three population-based cohorts from Asia, North America, and Europe, we observed consistent early decline in non-memory domains followed by later memory decline. These findings support evaluation of midlife cognitive monitoring and life-course approaches to brain health.
CITATION:
Jan Sebastian Novotný ; Sivan Klil-Drori ; Yonas Endale Geda ; Ziad Nasreddine ; Gorazd Bernard Stokin (2026): Timing of cognitive decline onset and life-course trajectories A pooled longitudinal analysis of 14,389 adults across three cohorts. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100649
INCREASING CARDIOVASCULAR DISEASE RISK PREDICTS FASTER COGNITIVE DECLINE: A BAYESIAN ANALYSIS OF A COHORT OF ADULTS IN RURAL WEST TEXAS
Chathurika S. Dhanasekara, Chanaka N. Kahathuduwa, Chanaka N. Kahathuduwa
Show summaryHide summary
BACKGROUND: Cardiovascular disease (CVD) is a major risk factor for cognitive decline and dementia. We examined whether a higher atherosclerotic cardiovascular disease (ASCVD) risk is associated with faster cognitive decline in Project FRONTIER, a rural cohort.
METHODS: Participants were aged ≥40 years without baseline CVD and completed two study visits. Primary outcomes were the RBANS Total Score and its domains; secondary outcomes were Executive Interview 25, verbal fluency, Clock Drawing Test (CLOX), and Trail Making Test (TMT) A and B. Primary exposure was the 10-year ASCVD risk per AHA PREVENT equations. We fitted Bayesian mixed-effects models to estimate the interaction between time (in years) and ASCVD risk, adjusting for covariates using brms package in R.
RESULTS: We analyzed data of 383 participants (age 57.74 ± 11.4 years; 75.5 % female; 59.8 % Hispanic; median follow-up 3.00 years, IQR: 2.67–3.64). The time×ASCVD risk interaction for RBANS Total was credibly negative (β = −1.22 points/year per 10 % higher risk, 95 % CrI −1.87 to −0.58). Strongest domain-specific effects were for attention (β = −1.25; 95 % CrI −2.14 to −0.37) and delayed memory (β = −1.36; 95 % CrI −2.16 to −0.05). CLOX suggested a credibly negative interaction (β = −0.39; 95 % CrI −0.62 to −0.16), and TMT-A showed a credibly positive interaction (β = +2.85 s/year; 95 % CrI 1.28 to 4.41).
DISCUSSION: In this rural cohort, a higher 10-year ASCVD risk was associated with faster decline in global cognition, particularly attention and delayed memory, supporting the potential value of cardiovascular risk monitoring and modification to preserve cognitive function.
CITATION:
Chathurika S. Dhanasekara ; Chanaka N. Kahathuduwa ; Volker Neugebauer (2026): Increasing cardiovascular disease risk predicts faster cognitive decline: A Bayesian analysis of a cohort of adults in rural West Texas. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100651
PSYCHOLOGICAL ADVERSITIES AND EPIGENETIC AGEING IN MIDLIFE AND OLDER AGE: A SYSTEMATIC REVIEW AND META-ANALYSIS
Jiuyu Guo, Jiatong Shan, Kaisy Xinhong Ye, Wei Liang, Yanyu Wang, Eng-Tat Ang, Tih-Shih Lee, John Suckling, Andrea B. Maier, Lei Feng
Show summaryHide summary
BACKGROUND: Epigenetic modification is a hallmark of aging that encloses physiological information relevant to health and longevity and has been used to construct epigenetic clocks that estimate epigenetic age acceleration (EAA) to monitor population health across the life span. Psychological adversities (PA) are recognized contributors to poor health; however, their potential role in EAA remains insufficiently understood in older adults.
OBJECTIVE: This study systematically reviews and meta-analyzes the association between PA and EAA from midlife onward.
METHODS: Eligible literatures were indexed in five databases up to July 2025. Study quality was assessed using an adapted Newcastle-Ottawa scale. Meta-analyses were performed using random-effects models, followed by post hoc and sensitivity analyses to assess robustness.
RESULTS: Twenty-two studies were included, of which fifteen were classified as high quality. Irrespective of the type of psychological adversity, positive associations were consistently observed for second-generation epigenetic clocks (PhenoAge and GrimAge). Meta-analyses revealed that greater loneliness (β = 0.07, 95 % CI [0.06, 0.08], I2 = 0 %, p = 0.002), depression (β = 0.08, 95 % CI [0.04, 0.13], I2 = 55.2 %, p = 0.003), and stress (β = 0.10, 95 % CI [0.03, 0.16], I2 = 68.4 %, p = 0.009) were each associated with higher EAA.
CONCLUSIONS: Psychosocial stress, depression, and loneliness are each associated with accelerated aging from midlife onward. Notable gaps include the lack of studies examining anxiety and underrepresentation of non-Western population. Whether alleviating psychological adversities translates into decelerated aging trajectories requests future intervention studies.
CITATION:
Jiuyu Guo ; Jiatong Shan ; Kaisy Xinhong Ye ; Wei Liang ; Yanyu Wang ; Eng-Tat Ang ; Tih-Shih Lee ; John Suckling ; Andrea B. Maier ; Lei Feng (2026): Psychological adversities and epigenetic ageing in midlife and older age: A systematic review and meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100650
JPAD Volume 13, N°08 - 2026
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)
Show summaryHide summary
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)
Show summaryHide summary
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)
Show summaryHide summary
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)
Show summaryHide summary
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)
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