Ahead of print articles
COMPREHENSIVE SOCIAL DETERMINANTS OF HEALTH AND BRAIN HEALTH IN MIDLIFE
Christina S. Dintica, Julia Cheunkarndee, R. Nick Bryan, Lenore J. Launer, Kristine Yaffe
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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
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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
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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
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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
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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
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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
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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
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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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
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
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INTRODUCTION: 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
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
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BACKGROUND: 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
DIETARY PATTERNS AND ALZHEIMER\'S DISEASE: EAST-WEST PERSPECTIVES AND FUTURE INTERVENTION STRATEGIES
Wanlu Jiang, Yijia Lin, Qihao Guo, Ya Miao
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Among 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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
EDITORIAL: TAU-ING AND FRO-ING: THE TANYCYTIC SHUTTLE IN NEURODEGENERATION
Vincent Prévot, Markus Schwaninger, Ruben Nogueiras, S. Rasika
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After 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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
LETTER TO THE EDITOR: THE GENERALIZABILITY GAP: ANTICOAGULANT EXCLUSIONS AND THE \"ENHANCED SAFETY\" OF DONANEMAB IN THE EU-ELIGIBLE POPULATION
Azan Ijaz, Ghulam Mohyudin
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CITATION:
Azan Ijaz ; Ghulam Mohyudin (2026): Letter to the Editor: The generalizability gap: anticoagulant exclusions and the "Enhanced Safety" of donanemab in the EU-eligible population. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100628
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
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BACKGROUND: 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
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
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BACKGROUND & 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
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
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BACKGROUND: 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
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
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BACKGROUND: 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
COMBINED EFFECT OF ANXIETY DISORDER AND INSOMNIA ON THE RISK OF INCIDENT ADRD DIAGNOSIS
SangNam Ahn, Joanne Salas, Jinmyoung Cho, Jeffrey F. Scherrer
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BACKGROUND: Anxiety disorders and insomnia are common modifiable conditions in older adults, but their independent and combined effects on the risk of incident Alzheimer’s disease and related dementias (ADRD) remain unclear.
OBJECTIVES: To estimate the independent and combined associations of anxiety disorders and insomnia with the risk of incident ADRD.
DESIGN: Retrospective cohort study using an intention-to-treat approach with a 10-year follow-up period (2014–2023).
SETTING: De-identified electronic health record (EHR) data from 70 participating healthcare organizations within the TriNetX Research Network.
PARTICIPANTS: Adults aged ≥50 years without prior dementia who had regular ambulatory care during a three-year baseline period (n = 1,868,790).
MEASUREMENTS: Anxiety and insomnia were identified using ICD-based algorithms and categorized into four exposure groups: neither condition, anxiety only, insomnia only, and both. Incident ADRD was defined by two or more diagnostic codes within 12 months. Entropy balancing controlled for confounding, and weighted Cox proportional hazards models estimated hazard ratios (HRs).
RESULTS: At baseline, 4.1% had anxiety only, 3.8% had insomnia only, and 1.1% had both. Over follow-up, 2.3% developed ADRD. In weighted models, insomnia alone (HR: 1.12; 95% CI: 1.06–1.19), anxiety alone (HR: 1.49; 95% CI: 1.39–1.60), and co-occurring anxiety and insomnia (HR: 1.31; 95% CI: 1.06–1.62) were each associated with higher ADRD risk compared with neither condition. No significant effect modification by age, sex, or race was observed.
CONCLUSIONS: Anxiety and insomnia independently increase ADRD risk, though insomnia's contribution is very modest compared to the primary association demonstrated by anxiety. Co-occurrence does not confer additional risk beyond anxiety alone. Clinically, routine screening and treatment of anxiety and sleep disturbances represent actionable, broadly applicable strategies for ADRD prevention and healthy cognitive aging.
CITATION:
SangNam Ahn ; Joanne Salas ; Jinmyoung Cho ; Jeffrey F. Scherrer (2025): Combined effect of anxiety disorder and insomnia on the risk of incident ADRD diagnosis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100621
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
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BACKGROUND: In the European Union (EU), donanemab is indicated in adults with early symptomatic Alzheimer’s disease who are apolipoprotein E ε4 non-carriers or heterozygotes. Among these, patients without superficial siderosis at baseline, uncontrolled hypertension, or anticoagulant use are eligible.
OBJECTIVE: To assess efficacy and safety of donanemab in the EU-eligible population.
METHODS: A post-hoc conservative hybrid imputation method was implemented for clinical efficacy analyses during the TRAILBLAZER-ALZ 2 placebo-controlled period. In the 78-week long-term extension (LTE) participants in the early-start (randomised to donanemab) and delayed-start (randomised to placebo with donanemab initiation during the LTE) groups were compared to a propensity-weighted external control. Participants were switched to placebo after meeting amyloid-based treatment course completion criteria.
RESULTS: By 76 weeks, donanemab-treated participants in the EU-eligible population had a mean Clinical Dementia Rating Scale (CDR)-Sum of Boxes change from baseline difference from placebo of -0.7 points (95% confidence interval, -1.0, -0.4) and a 40.3% lower risk of disease progression to the next stage (per CDR-Global score). Treatment benefit increased over 154 weeks for non-carriers and heterozygotes, including those meeting treatment course completion criteria by 52 or 76 weeks. In the placebo-controlled period, 119 (19.5%) and 49 (8.0%) donanemab-treated eligible participants experienced amyloid-related imaging abnormalities-edema/effusion and infusion-related reactions, respectively. Safety findings were similar among donanemab-treated participants in the placebo-controlled period and LTE delayed-start group.
CONCLUSIONS: Consistent with previous TRAILBLAZER-ALZ 2 and LTE findings, donanemab significantly slowed disease progression compared to controls with a manageable safety profile in non-carriers and heterozygotes.
CITATION:
Frank Jessen ; Grazia Dell’Agnello ; Jennifer A. Zimmer ; Christophe Sapin ; Sascha Dichter ; Erin Doty ; Stéphane Epelbaum ; Cynthia D. Evans ; Paula M. Hauck ; Rashna Khanna ; Dawn A. Brooks ; John R. Sims ; Federica Agosta ; Alzheimer’s Disease Neuroimaging Initiative (ADNI) (2025): Efficacy and safety of donanemab in the European eligible population: TRAILBLAZER-ALZ 2 post-hoc analyses. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100605
SUBJECTIVE COGNITION TRAJECTORIES, ALZHEIMER BIOMARKERS, AND INCIDENT MILD COGNITIVE IMPAIRMENT
Elizabeth Kuhn, Luca Kleineidam, Melina Stark, Oliver Peters, Julian Hellmann-Regen, Lukas Preis, Daria Gref, Josef Priller, Eike Jakob Spruth, Maria Gemenetzi, Anja Schneider, Klaus Fliessbach, Jens Wiltfang, Claudia Bartels, Niels Hansen, Ayda Rostamzadeh, Emrah Düzel, Wenzel Glanz, Enise Incesoy, Katharina Buerger, Daniel Janowitz, Sophia Stöcklein, Robert Perneczky, Boris-Stephan Rauchmann, Stefan J. Teipel, Ingo Kilimann, Christoph Laske, Sebastian Sodenkamp, Annika Spottke, Marie Kronmüller, Sandra Roeske, Frederic Brosseron, Alfredo Ramirez, Matthis Synofzik, Matthias C. Schmid, Frank Jessen, Michael Wagner, Alzheimer’s Disease Neuroimaging Initiative, DELCODE study group
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BACKGROUND: Subjective cognitive decline is common in older adults and may represent an early clinical signal along the Alzheimer’s disease continuum. The clinical relevance of longitudinal changes in subjective cognitive decline remains unclear.
OBJECTIVES: To determine whether trajectories of self- or study partner-reported cognitive decline predict progression to mild cognitive impairment and reflect Alzheimer’s disease-specific biological patterns.
DESIGN, SETTING, PARTICIPANTS: Data were pooled from two observational cohorts. Cognitively unimpaired participants with baseline amyloid status, repeated assessments of subjective cognitive decline, and clinical follow-up were included. The study included 770 participants with a median follow-up of 5.0 years (interquartile range 4.0–7.0).
MEASUREMENTS: Subjective cognitive decline was assessed using the Everyday Cognition questionnaire completed by participants and study partners. Linear mixed-effects models examined associations with amyloid status and progression to mild cognitive impairment. Cox proportional hazards models tested whether one-year changes predicted progression.
RESULTS: Amyloid-positive participants and those who progressed to mild cognitive impairment showed steeper increases in self- and study partner-reported cognitive difficulties over time. Among amyloid-positive participants, only increases in study partner-report differentiated progressors from non-progressors. One-year increases in study partner-report predicted a higher risk of mild cognitive impairment compared with unchanged scores (hazard ratio 3.24; 95% confidence interval 1.73–6.07]), with effects confined to amyloid-positive participants.
CONCLUSIONS: Short-term increases in study partner-reported cognitive difficulties identify amyloid-positive cognitively unimpaired older adults at increased risk of near-term progression to mild cognitive impairment. Longitudinal monitoring using study partner reports may provide a low-burden and clinically relevant approach for early risk stratification and surveillance in aging populations.
CITATION:
Elizabeth Kuhn ; Luca Kleineidam ; Melina Stark ; Oliver Peters ; Julian Hellmann-Regen ; Lukas Preis ; Daria Gref ; Josef Priller ; Eike Jakob Spruth ; Maria Gemenetzi ; Anja Schneider ; Klaus Fliessbach ; Jens Wiltfang ; Claudia Bartels ; Niels Hansen ; Ayda Rostamzadeh ; Emrah Düzel ; Wenzel Glanz ; Enise Incesoy ; Katharina Buerger ; Daniel Janowitz ; Sophia Stöcklein ; Robert Perneczky ; Boris-Stephan Rauchmann ; Stefan J. Teipel ; Ingo Kilimann ; Christoph Laske ; Sebastian Sodenkamp ; Annika Spottke ; Marie Kronmüller ; Sandra Roeske ; Frederic Brosseron ; Alfredo Ramirez ; Matthis Synofzik ; Matthias C. Schmid ; Frank Jessen ; Michael Wagner ; for theAlzheimer’s Disease Neuroimaging Initiative ⁎and theDELCODE study group (2025): Subjective cognition trajectories, Alzheimer biomarkers, and incident mild cognitive impairment. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100609
MAPPING THE NATURE, TYPE, AND ASSOCIATION NETWORK OF SAFETY INCIDENTS AMONG INDIVIDUALS WITH COGNITIVE IMPAIRMENT IN CHINA: A LARGE-SCALE MULTICENTER CROSS-SECTIONAL STUDY
Ying Zhou, Guoping Peng, Zhengluan Liao, Huayan Liu, Jun Liu, Wang Liao, Qiumin Qu, Jingping Shi, Jieli Geng, Nan Zhi, Wenwei Cao, Yaying Song, Yang Zhang, Xiaohong Wang, Lin Wang, Yuan Zhu, Yan Zhou, Huali Wang, Yongan Sun, Rujing Ren, Hengge Xie, Gang Wang, representing ADC
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BACKGROUND: Patient safety critically influences both quality of life and disease progression in older adults with cognitive impairment, yet large-scale multicenter data remain scarce. This study aims to systematically analyze the types of safety incidents experienced by patients with Alzheimer’s disease and related cognitive impairments, and explore the network associations of different safety incidents.
METHODS: Initiated by the Alzheimer's Disease China (ADC), this survey recruited 1057 older individuals with Alzheimer’s and related cognitive impairments, along with their families, across 31 provinces, autonomous regions, and municipalities. The safety incidents evaluated in this study included falls, getting lost, medication errors, verbal aggression, physical aggression, household fire, aspiration, and choking. Incidence rates for overall and specific safety incidents were calculated. Correlation analyses and network analysis were performed to examine relationships between safety incidents.
RESULTS: A high proportion (73.5%) of participants reported at least one safety incident in the past year, with over one-third (36.0%) experiencing three or more concurrent incidents. Medication errors (55.9%) and verbal aggression (39.6%) were most frequent, followed by falls (32.5%) and physical aggression (22.7%). Incidence rates varied significantly by cognitive impairment stage, care setting, and geographic region. Network analysis highlighted medication errors and getting lost as central nodes bridging other incidents.
CONCLUSIONS: This study reveals an alarmingly high incidence of safety incidents among cognitively impaired patients, affecting their physical, psychological, and familial well-being. A collaborative, multidisciplinary effort involving healthcare professionals, family caregivers, fire and police emergency responders, and public health policymakers is essential to develop individualized safety strategies aligned with patient needs and contextual considerations.
CITATION:
Ying Zhou ; Guoping Peng ; Zhengluan Liao ; Huayan Liu ; Jun Liu ; Wang Liao ; Qiumin Qu ; Jingping Shi ; Jieli Geng ; Nan Zhi ; Wenwei Cao ; Yaying Song ; Yang Zhang ; Xiaohong Wang ; Lin Wang ; Yuan Zhu ; Yan Zhou ; Huali Wang ; Yongan Sun ; Rujing Ren ; Hengge Xie ; Gang Wang ; representing ADC (2025): Mapping the nature, type, and association network of safety incidents among individuals with cognitive impairment in China: a large-scale multicenter cross-sectional study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100606
IDENTIFICATION OF A CD44-DEPENDENT CONTROL OF ASTROCYTIC AUTOPHAGIC ACTIVITY IN ALZHEIMER’S DISEASE
Haiyan Wang, Ying Long, Yu Tang, Lijie Duan, Zijie Wang, Shuzhen Zhang, Yanqing Yin, Jiawei Zhou, Wenjuan Wu, Chunjiu Zhong
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BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. Despite extensive research, the precise molecular mechanisms driving AD pathogenesis remain incompletely understood. This study sought to identify robust molecular targets and cellular basis underlying AD progression.
METHODS: We performed a systematic analysis of cross-regional transcriptomic datasets from AD patients, integrating differential expression analysis across 14 Gene Expression Omnibus (GEO) datasets with cross-regional intersection mapping. Single-nucleus RNA sequencing (snRNA-seq) was employed to resolve cell-type-specific expression patterns. Furthermore, cellular communication analysis and functional enrichment of astrocyte-specific genes were conducted. The biological role of the identified candidate was validated in vitro using Aβ42 oligomer-treated primary astrocytes via siRNA-mediated knockdown and plasmid-driven overexpression, with autophagic activity assessed through LC3-II and p62 expression.
RESULTS: The transmembrane glycoprotein receptor CD44 was identified as consistently upregulated across AD-vulnerable brain regions, including the temporal cortex, frontal cortex, entorhinal cortex, and hippocampus. snRNA-seq analysis identified this upregulation primarily to astrocytes. Intercellular signaling analysis indicated that the CD44-SPP1 axis enhanced astrocyte-glial crosstalk. Functional enrichment analysis linked astrocytic CD44 to the modulation of autophagy pathways. In vitro experiments demonstrated that CD44 knockdown promoted autophagic activation (increased LC3-II and decreased p62), whereas CD44 overexpression suppressed autophagic activity.
CONCLUSION: Our findings establish CD44 as a pivotal regulator of astrocytic autophagy in AD, highlighting its potential as a novel therapeutic target.
CITATION:
Haiyan Wang ; Ying Long ; Yu Tang ; Lijie Duan ; Zijie Wang ; Shuzhen Zhang ; Yanqing Yin ; Jiawei Zhou ; Wenjuan Wu ; Chunjiu Zhong (2025): Identification of a CD44-dependent control of astrocytic autophagic activity in Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100601
EFFECT OF ACCELEROMETER-MEASURED PHYSICAL ACTIVITY ON THE ASSOCIATION BETWEEN ATRIAL FIBRILLATION AND RISK OF DEMENTIA
Le Li, Mengtong Xu, Lingmin Wu, Zhicheng Hu, Limin Liu, Likun Zhou, Minghao Zhao, Yulong Xiong, Zhenhao Zhang, Lihui Zheng, Ligang Ding, Yan Yao
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BACKGROUND: Atrial fibrillation (AF) independently increases dementia risk, but whether accelerometer-measured physical activity (PA) modifies this association remains unquantified, particularly against self-reported PA limitations.
METHODS: Prospective analysis of 91,795 UK Biobank participants with valid accelerometer data (median age 57, 42.9 % male; 2800 with baseline AF). We categorized whether measured activity met the standard recommendation [moderate-to-vigorous physical activity (MVPA) >_150 min/week]. Questionnaire-derived MVPA data from 353,643 UK Biobank participants (median age 57, male: 46.7 %) between 2006 and 2010 were used for validation. The primary outcome was the diagnosis of incident all-cause dementia. We also assessed correlation between accelerometer-derived and self-reported activity.
RESULTS: Over 7.6-year median follow-up, AF was significantly associated with a higher dementia risk [Adjusted hazard ratio (aHR): 1.76, 95 % confidential interval (CI): 1.51–2.05]. Guideline-adherent PA was associated with a lower AF-related dementia risk to non-significance (aHR: 1.36, 95 %CI: 0.96–1.91). Moreover, PA may be associated with higher protection effect on dementia risk in AF patients (aHR: 0.55, 95 % CI: 0.33–0.92) than in non-AF (aHR: 0.81, 95 % CI: 0.69–0.96), although without statistical difference (Pinteraction = 0.213). Correlation between accelerometer-derived and selfreported MVPA was weak (Spearman r = 0.155, 95 % CI: 0.148–0.162). Self-reported activity was not associated with a decreased risk of dementia in both AF and non-AF participants.
CONCLUSION: Higher accelerometer-measured PA is associated with lower AF-associated dementia risk. Future prospective studies with extended follow-up and serial activity monitoring are needed to confirm these findings.
CITATION:
Le Li ; Mengtong Xu ; Lingmin Wu ; Zhicheng Hu ; Limin Liu ; Likun Zhou ; Minghao Zhao ; Yulong Xiong ; Zhenhao Zhang ; Lihui Zheng ; Ligang Ding ; Yan Yao (2025): Effect of accelerometer-measured physical activity on the association between atrial fibrillation and risk of dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100603
LETTER TO THE EDITOR : BEYOND RECOGNITION: REFINING THE ASSESSMENT OF PUBLIC KNOWLEDGE AND RISK PERCEPTION IN DEMENTIA PREVENTION
Zhiyan Xie, Jun Su, Tao Liao
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CITATION:
Zhiyan Xie ; Jun Su ; Tao Liao (2025): Letter to the Editor: Beyond recognition: Refining the assessment of public knowledge and risk perception in dementia prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100602
CLINICAL AND BIOLOGICAL RELEVANCE OF OBJECTIVELY-DEFINED SUBTLE COGNITIVE DECLINE IN ALZHEIMER’S DISEASE: A NARRATIVE REVIEW OF NEUROIMAGING, BIOMARKER, AND CLINICAL PROGRESSION STUDIES
Amanda I. Gonzalez, Jairo E. Martinez, Averi Giudicessi, Meredith Rowe, Vivian Ku, Catarina Tristão-Pereira, Bing He, Vincent Malotaux, Yakeel T. Quiroz
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Preclinical Alzheimer’s Disease stages represent possible targets for disease-modifying intervention as well as opportunity for early identification of risk for future decline. Recent research has explored the use of objectively-defined subtle cognitive decline (Obj-SCD), an emerging classification that may identify individuals at risk for neurodegeneration before the onset of mild cognitive impairment (MCI). The Edmonds/Thomas actuarial Obj‐SCD criteria (> 1 SD below expectations, single cognitive test impaired per domain) aims to capture those who exhibit minimal cognitive difficulties that do not meet a MCI or dementia diagnosis. Given the novelty of the Obj-SCD classification, this narrative review provides an overview of neuroimaging, biomarker, and clinical progression studies to evaluate its biological and clinical significance. Using fluid-based biomarkers, neuroimaging, and longitudinal designs, studies have indicated that the Obj-SCD classification has the potential to capture AD-related pathological changes detectable before the clinical onset of MCI. In particular, recent studies indicate a unique pathological profile of Obj-SCD, differentiating it from the cognitively unimpaired and MCI stages. Studies comparing Obj-SCD and subjective cognitive complaints show that the Obj-SCD criteria may be more closely associated to early AD pathology. While the existing literature is limited, findings uphold Obj-SCD as a sensitive classification able to identify individuals at risk for future cognitive impairment. Studies on Obj-SCD indicate utility in research settings, although it faces challenges regarding its clinical implementation and effectiveness.
CITATION:
Amanda I. Gonzalez ; Jairo E. Martinez ; Averi Giudicessi ; Meredith Rowe ; Vivian Ku ; Catarina Tristão-Pereira ; Bing He ; Vincent Malotaux ; Yakeel T. Quiroz (2025): Clinical and biological relevance of objectively-defined subtle cognitive decline in Alzheimer’s disease: a narrative review of neuroimaging, biomarker, and clinical progression studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100604
JPAD Volume 13, N°07 - 2026
EDITORIAL: ELIGIBILITY OF MEN VS. WOMEN IN ALZHEIMER’S TRIALS: INCLUSIVE VS. REPRESENTATIVE
Joshua D. Grill, Daniel L. Gillen
J Prev Alz Dis 2026;7(13)
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CITATION:
Joshua D. Grill ; Daniel L. Gillen (2025): Editorial: Eligibility of men vs. women in Alzheimer’s trials: Inclusive vs. representative. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100625
TOP FIVE ALZHEIMER DISEASE TRIAL ELIGIBILITY CRITERIA FAVOR MEN COMPARED TO WOMEN IN A CLINIC-BASED COHORT
Lieza G. Exalto, Siti S. Syaziyah, Xiaotian T Fang, Niels D. Prins, Sietske A.M. Sikkes, Wiesje M. van der Flier, Everard G.B. Vijverberg, Yvonne M.F. Lim
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryBACKGROUND: Less women participate in Alzheimer Disease (AD) trials compared to their estimated representation in the global dementia population.
OBJECTIVES: We aimed to apply five most commonly used eligibility criteria to a real-world memory clinic population to compare male and female eligibility according to these criteria.
DESIGN: Observational.
SETTING: Memory clinic setting.
PARTICIPANTS: Consecutive patients (2000–2024) from Amsterdam Dementia Cohort with a diagnosis of mild cognitive impairment (MCI) or AD (n = 3835).
MEASUREMENTS: Free-text eligibility criteria of n = 608 phase II and III AD drug trials were downloaded from ClinicalTrials.gov (March 28, 2025). A machine-learning model was trained and validated to extract all eligibility criteria. Next the criteria were applied on observational real world data from on memory clinic diagnostic work-up.
RESULTS: Top 5 most common AD clinical trial eligibility criteria were 1) no other central nervous system disorder related to cognitive impairment (84%), 2) participation of a caregiver (72%), 3) MMSE (66%, range 20–30), 4) no comorbidities, specifically vascular and mental health (62%), 5) no contra-indications for study procedures such as lumbar puncture, MRI and PET (59%). Applying the abovementioned criteria results in 33% of men and 23% of women remaining eligible (p<.001). Main reason for non-eligibility is caretaker absence (applicable for 20% of men and 38% of women) and low MMSE (32% of man and 54% of women).
CONCLISION: Based on five commonly used eligibility criteria of AD clinical trials, women in our clinic-based cohort are less eligible for participation in AD drug trials than men. This discrepancy was mainly attributed to lack of caregiver presence and lower MMSE at presentation. These results provide clues for trial design to facilitate more equal inclusion of women.
CITATION:
Lieza G. Exalto ; Siti S. Syaziyah ; Xiaotian T Fang ; Niels D. Prins ; Sietske A.M. Sikkes ; Wiesje M. van der Flier ; Everard G.B. Vijverberg ; Yvonne M.F. Lim (2025): Top five Alzheimer Disease trial eligibility criteria favor men compared to women in a clinic-based cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100580
EDITORIAL: BEYOND TARGET ENGAGEMENT: RNA THERAPEUTICS AND THE NEUROIMMUNE CHALLENGE IN TAUOPATHIES
Elizabeth Anne Breen
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryRecent advances in RNA-based therapeutics have generated considerable interest as a strategy for targeting tau pathology in Alzheimer's disease and related tauopathies. In their review, Rajbanshi and colleagues provide a comprehensive overview of emerging RNA therapeutic modalities, translational challenges, and ongoing clinical development efforts. This commentary discusses the promise of RNA-based approaches within the broader context of contemporary neurodegeneration research, highlighting the persistent disconnect between molecular target engagement and meaningful clinical benefit. Emerging evidence suggests that successful disease modification may require consideration of neuroimmune dysfunction, biological heterogeneity, and disease stage in addition to molecular pathology. The future success of RNA therapeutics will likely depend not only on achieving precise modulation of tau biology but also on translating these advances into sustained cognitive and functional benefit for patients.
CITATION:
Ece Bayram (2025): Editorial: Beyond target engagement: RNA therapeutics and the neuroimmune challenge in tauopathies. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100626
RNA-BASED THERAPEUTICS FOR ALZHEIMER’S DISEASE AND RELATED TAUOPATHIES: CHALLENGES AND OPPORTUNITIES
Binita Rajbanshi, Ilaria Brentari, Michela Alessandra Denti, Jeffrey L. Cummings, Anuj Guruacharya
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryTauopathies are neurodegenerative diseases characterized by pathological tau protein accumulation. Though therapies involving monoclonal antibodies and small-molecule inhibitors have progressed, they have so far failed in multiple clinical trials, underscoring the need for innovative molecular approaches. RNA-based therapies offer an alternative disease-modifying approach by being able to target tau at its molecular origin. Diverse modalities, such as mRNA, ASO, RNAi, and SSO, offer distinct promises. Though their challenges are equally diverse, they also share common problems. This review examines the nascent field of RNA therapeutics for tauopathies, outlining emerging modalities, translational barriers, molecular targets, clinical trials, and patent trends.
CITATION:
Binita Rajbanshi ; Ilaria Brentari ; Michela Alessandra Denti ; Jeffrey L. Cummings ; Anuj Guruacharya (2025): RNA-based therapeutics for Alzheimer’s disease and related tauopathies: challenges and opportunities. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100585
EDITORIAL: TIME TO PAY ATTENTION TO SLEEP FOR ALZHEIMER’S DISEASE IN WOMEN
Ece Bayram
J Prev Alz Dis 2026;7(13)
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CITATION:
Ece Bayram (2025): Editorial: Time to pay attention to sleep for Alzheimer’s disease in women. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100624
SLEEP COMPLAINTS AND GENETIC RISK OF ALZHEIMER’S DISEASE IN OLDER WOMEN: ASSOCIATIONS WITH MEMORY AND TAU DEPOSITION
Kitty K Lui, Xin Wang, Melanie A Dratva, Ella T. Lifset, Jordan Stiver, Nadine C. Heyworth, Qian Shen, Michael Thomas, Pamela N. DeYoung, Atul Malhotra, Erin E. Sundermann, Sarah J. Banks
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryBACKGROUND: Emerging evidence point to a bidirectional relationship between sleep disturbances and Alzheimer’s disease (AD). Poor sleep may be an overlooked risk factor for older women, who are disproportionately affected by AD and report worse subjective sleep quality than men. High genetic AD risk—characterized by the polygenic hazard score (PHS), including apolipoprotein (APOE) ε4 carriership—may further compound the effects of disrupted sleep on AD, particularly for older women.
OBJECTIVE: This study examined the moderating effect of genetic AD risk on subjective sleep as it related to memory and tau burden in a sample of older women.
PARTICIPANTS: The sample consisted of older women (≥65 years old) from the Women Inflammation Tau Study.
MEASUREMENT: Participants completed the Pittsburgh Sleep Quality Index (PSQI), Rey Auditory Learning Test, and Brief Visuospatial Memory Test-Revised. They also underwent [18]F-MK6240 positron emission tomography. Tau burden was calculated in composite regions across Braak stages. Genetic risk groups were characterized by PHS stratified at the 75th percentile. PSQI global score × PHS group interactions on memory composite scores (N = 69) and tau burden (N = 63) were examined.
RESULTS: PSQI global score × PHS group interactions were observed on visual memory and pathological tau in Braak regions III/IV (ps<0.10). Poorer subjective sleep was associated with worse visual memory and greater limbic tau deposition only among higher genetic risk women (ps<0.04). No significant associations were observed for verbal memory or tau in Braak regions I/II or V/VI.
CONCLUSION: Older women with elevated genetic AD risk and subjective sleep difficulties may be at greater risk for visual memory deficits and tau burden in regions affected in early AD. This suggests that sleep complaints may represent a promising AD risk factor. Improving sleep may be a potential intervention target for AD mitigation and prevention, particularly for older women.
CITATION:
Kitty K Lui ; Xin Wang ; Melanie A Dratva ; Ella T. Lifset ; Jordan Stiver ; Nadine C. Heyworth ; Qian Shen ; Michael Thomas ; Pamela N. DeYoung ; Atul Malhotra ; Erin E. Sundermann ; Sarah J. Banks (2025): Sleep complaints and genetic risk of Alzheimer’s disease in older women: associations with memory and tau deposition. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2025.8
TETANUS, DIPHTHERIA AND PERTUSSIS VACCINATION AND RISK FOR INCIDENT DEMENTIA AMONG ADULTS WITH DOWN SYNDROME
Kimberly Schiel, Joanne Salas, Anjani Urban, Daniel F. Hoft, Jeffrey F. Scherrer
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryBACKGROUND: Adult vaccination is inversely associated with incident Alzheimer’s Disease and Related Dementias.
OBJECTIVES: We determined if Tetanus, Diphtheria and Pertussis (Tdap) vaccination was linked to incident Alzheimer’s Disease and dementia among adults with Down Syndrome, 50% of whom develop Alzheimer’s Disease by age 60.
DESIGN: This is a retrospective cohort study using TriNetX nationally distributed electronic health records from 2013 to 2024.
SETTING: Historical medical record data.
PARTICIPANTS: 5591 patients with Down Syndrome across the United States. Eligible patients were free of Alzheimer’s Disease and dementia prior to index. Index date could occur 1/1/2015 to 1/1/2020 allowing for 5 to 10 years of possible follow-up time.
MEASUREMENTS: Vaccination was measured using product name and procedure codes and Alzheimer’s Disease and dementias was defined by ICD-10 codes.
RESULTS: The mean age of the cohort was 50.0 (±8.3), 50.1% were female and 72.1% were White. After controlling for confounding, Tdap vaccination vs. remaining without Tdap vaccination was associated with lower Alzheimer’s Disease and dementia risk (HR=0.74; 95%CI:0.57–0.98).
CONCLUSIONS: In a cohort of patients with Down Syndrome, Tdap vaccination was associated with a 26% lower risk for Alzheimer’s Disease and dementia. This is a novel and important finding because existing studies of vaccination and reduced risk for Alzheimer’s Disease and dementia have been among cognitively intact adults. This study reveals benefits of vaccination even among those at high risk for Alzheimer’s Disease and dementia due to Down Syndrome. Future studies are needed to understand the mechanisms underlying this relationship.
CITATION:
Kimberly Schiel ; Joanne Salas ; Anjani Urban ; Daniel F. Hoft ; Jeffrey F. Scherrer (2025): Tetanus, diphtheria and pertussis vaccination and risk for incident dementia among adults with down syndrome. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100583
EPIGENETIC AGING AND BLOOD BASED NEURODEGENERATION MARKERS IN LASI-DAD
Jung Ki Kim, Thalida E. Arpawong, Bharat Thyagarajan, Jennifer A. Smith, Sithara Vivek, Scott Ratliff, Sharmistha Dey, Jinkook Lee, Eileen M. Crimmins
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryDNA methylation (DNAm)-based epigenetic clocks are emerging biomarkers of biological aging and have been linked to cognitive decline and dementia, but their relationship with blood-based neurodegenerative biomarkers remains understudied in low- and middle-income countries (LMIC). Using the Longitudinal Aging Study in India-Diagnostic Assessment of Dementia (LASI-DAD), we examined whether epigenetic aging was associated with levels and changes in neurodegenerative biomarkers among adults aged ≥60 years. Seven epigenetic clocks were derived from DNAm data and related to plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), phosphorylated tau 181 (pTau181), total tau, Amyloid-β (Aβ)42, Aβ40 and Aβ42/Aβ40 measured at two time points. Baseline accelerated epigenetic aging was associated with higher levels of neurodegenerative biomarkers, including pTau181, GFAP, and NfL, with more consistent associations with increases in GFAP and NfL for morbidity- and mortality-trained clocks. These findings support the utility of epigenetic clocks as scalable tools for identifying risk of neurodegeneration in LMIC settings.
CITATION:
Jung Ki Kim ; Thalida E. Arpawong ; Bharat Thyagarajan ; Jennifer A. Smith ; Sithara Vivek ; Scott Ratliff ; Sharmistha Dey ; Jinkook Lee ; Eileen M. Crimmins (2025): Epigenetic aging and blood based neurodegeneration markers in LASI-DAD. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100595
HYPERTENSION ACTS TOGETHER WITH AΒ PATHOLOGY IN LATE-LIFE TO PROMOTE MEMORY LOSS
Lucas U Da Ros, João Pedro Ferrari-Souza, Marco Antônio de Bastiani, Lucas A. Hauschild, Bruna Bellaver, Pamela C.L. Ferreira, Douglas Teixeira Leffa, Guilherme Povala, Firoza Z. Lussier, Mira Chamoun, Gleb Bezgin, Andrea L. Benedet, Nesrine Rahmouni, Arthur C. Macedo, Kaj Blennow, Nicholas Ashton, Henrik Zetterberg, Wyllians Vendramini Borelli, Diogo O. Souza, Tharick A. Pascoal, Pedro Rosa-Neto, Eduardo R. Zimmer, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryMidlife hypertension (HTN) contributes to cognitive decline in Alzheimer's disease (AD). However, the exact effect of late-life HTN on the AD pathology and on cognitive decline is still controversial. Here, we aimed to assess the impact of HTN and AD pathology in cognitively unimpaired (CU) individuals over 65 years of age on longitudinal cognitive decline. We evaluated 637 CU individuals from two independent cohorts (475 CU individuals from the ADNI cohort; and 162 CU individuals from the TRIAD cohort), with a follow-up of up to 6 years. Linear mixed-effects models showed that HTN and Aβ acted together to promote longitudinal cognitive decline, especially memory loss, in a synergistic way, with a dose-dependent association of blood pressure and Aβ pathology. Hence, HTN in late-life confers additional risk for cognitive decline, particularly for memory loss, in CU individuals at risk of developing dementia due to AD and is a potential modifiable risk factor even at older age.
CITATION:
Lucas U Da Ros ; João Pedro Ferrari-Souza ; Marco Antônio de Bastiani ; Lucas A. Hauschild ; Bruna Bellaver ; Pamela C.L. Ferreira ; Douglas Teixeira Leffa ; Guilherme Povala ; Firoza Z. Lussier ; Mira Chamoun ; Gleb Bezgin ; Andrea L. Benedet ; Nesrine Rahmouni ; Arthur C. Macedo ; Kaj Blennow ; Nicholas Ashton ; Henrik Zetterberg ; Wyllians Vendramini Borelli ; Diogo O. Souza ; Tharick A. Pascoal ; Pedro Rosa-Neto ; Eduardo R. Zimmer ; for theAlzheimer’s Disease Neuroimaging Initiative (): Hypertension acts together with Aβ pathology in late-life to promote memory loss. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100579
INTERACTION OF DIET AND PHYSICAL ACTIVITY ON DEMENTIA RISK: THE ROTTERDAM STUDY
Muhammed Lamin Sambou, M. Arfan Ikram, M. Kamran Ikram, Jeremy A. Labrecque, Frank J. Wolters
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryBACKGROUND: Diet and physical activity have been reported as independent risk factors for dementia, but few published studies have investigated the interactive effects of the two on dementia risk. Understanding their synergism could help shape more effective prevention strategies. Therefore, we assessed the potential interactions between MIND diet adherence and physical activity on the long-term risk of incident dementia in the population-based Rotterdam Study.
METHODS: Between 2009–2013, 5016 participants of the population-based Rotterdam Study were recruited (mean age 69.76 years, 57.9% women). All participants filled in questionnaires regarding their adherence to the MIND diet and time spent on moderate to vigorous physical activity (Metabolic Equivalent of Task [MET] hours per week). Participants were subsequently followed for incident dementia until January 1, 2021. We applied multivariable Cox regression models to assess interaction on both additive and multiplicative scales.
RESULTS: Median values were 7.5 for the MIND diet score and 28.0 for MET hours per week. Of all 5016 participants, 2718 (54.2%) adhered to a high MIND diet score (≥7.5), and 2513 (50.1%) reached at least 28.0 MET hours per week. During a mean follow-up of 6.6 years, 365 participants (7.8%) developed dementia. Both higher physical activity and higher MIND-diet score were independently associated with a lower risk of dementia, but there was no significant interaction on the additive scale (RERI [95%CI]=-0.42 [-1.26 to 0.12]), nor on the multiplicative scale (HRinteraction=0.71 [0.46–1.09]). Sex-stratified analysis suggested a negative interaction between exposures in women, but not in men.
CONCLUSION: Better adherence to the MIND-diet and higher levels of physical activity were each associated with a reduced risk of dementia, but overall there was no indication that their joint effects were greater than the product or sum of their individual parts. Potential sex differences warrant further exploration in different populations.
CITATION:
Muhammed Lamin Sambou ; M. Arfan Ikram ; M. Kamran Ikram ; Jeremy A. Labrecque ; Frank J. Wolters (2025): Interaction of diet and physical activity on dementia risk: the Rotterdam study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100594
NEUROPSYCHIATRIC SYMPTOMS AND DEMENTIA DEVELOPMENT: A 15-YEAR POPULATION-BASED STUDY
Francesca Remelli, Giulia Grande, Serhiy Dekhtyar, Erika J Laukka, Caterina Trevisan, Stefano Volpato, Laura Fratiglioni, Federico Triolo
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryBACKGROUND: Mild Behavioral Impairment (MBI) has been proposed to detect neuropsychiatric symptoms (NPS) associated with dementia development, but evidence from population-based settings is limited.
OBJECTIVES: To (i) investigate the association between NPS in late life and the onset of dementia over 15 years in community-dwelling older adults, and (ii) test the interplay of NPS and Cognitive Impairment, No Dementia (CIND) in dementia development.
METHODS: 2597 dementia-free individuals aged 60+ from a longitudinal population-based cohort underwent cognitive assessments over 15 years. Thirty clinically-assessed NPS were mapped into five domains and, within each domain, a z-score was computed from the sum of the NPS’s points. MBI was identified when the z-score was above 1.5 standard deviations (SDs) in at least one of 5 neuropsychiatric domains. Based on a cognitive battery, CIND was defined as scoring ≥1.5 SDs below age-specific means in at least one cognitive domain. Dementia was diagnosed by DSM-IV criteria following standardized procedures.
RESULTS: MBI, present in 16.1% of the sample, was associated with a higher hazard of incident dementia over 15 years (multi-adjusted hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.31–2.17). Decreased motivation and social inappropriateness were the domains associated with incident dementia (HR 2.23, 95%CI 1.59–3.14 and HR 3.29, 95%CI 1.83–5.94, respectively). Compared to those with neither, individuals with either MBI (HR 1.37, 95%CI 1.00–1.90) or CIND (HR 2.22, 95%CI 1.73–2.84) had increased dementia incidence, especially when co-occurring (HR 4.41, 95%CI 3.04–6.39).
CONCLUSIONS: Late life NPS, especially with co-occurring cognitive impairment, was associated with a higher dementia incidence.
CITATION:
Francesca Remelli ; Giulia Grande ; Serhiy Dekhtyar ; Erika J Laukka ; Caterina Trevisan ; Stefano Volpato ; Laura Fratiglioni ; Federico Triolo (2025): Neuropsychiatric symptoms and dementia development: a 15-year population-based study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100596
PLASMA BRAIN-DERIVED P-TAU217 OUTPERFORMS OTHER P-TAU SPECIES IN DETECTING ABNORMAL BRAIN AMYLOID IN AN ASIAN COHORT OF OLDER PEOPLE WITH CEREBROVASCULAR DISEASE BURDEN
Joyce R. Chong, Saima Hilal, Narayanaswamy Venketasubramanian, Michael Schöll, Nicholas J. Ashton, Henrik Zetterberg, Christopher P. Chen, Mitchell K.P. Lai
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryBACKGROUND: Plasma brain derived-p-Tau217 (BD-p-Tau217) may outperform total-p-Tau217 in detecting brain amyloid burden and warrants evaluation.
OBJECTIVES: To perform head-to-head comparison of plasma BD- as well as total-p-Tau181, p-Tau217 and p-Tau231 for detecting beta-amyloid positivity (Aβ+), evaluate reference ranges for Aβ+, and assess the prognostic utility of BD-p-Tau217 reference ranges.
DESIGN: Observational study.
SETTING: Participants recruited from memory clinics and the community in Singapore.
PARTICIPANTS: 213 participants, including 44 cognitively normal, 107 cognitively impaired no dementia, and 62 dementia (mean [SD] age, 73 [1] years; 121 females).
MEASUREMENTS: Amyloid status (Aβ- [n = 139] vs Aβ+ [n = 74]) was determined by positron emission tomography (PET). Plasma BD-p-Tau and total-p-Tau were measured using the NULISAseq™ CNS Disease Panel 120. The diagnostic performance for detecting Aβ+, reference ranges (three-range: 95% specificity/95% sensitivity); binary: maximizing Youden index), and the prognostic performance of p-Tau biomarkers were evaluated.
RESULTS: Plasma BD-p-Tau217 (AUC = 0.965) outperformed other BD- and total-p-Tau species in detecting PET Aβ+ (AUC = 0.823–0.937; all p ≤ 0.008). Using a three-range reference, BD-p-Tau217 achieved positive predictive value (PPV) and negative predictive value (NPV) of 90% and 97%, respectively. Proportion of participants in the intermediate-risk group was 7% (n = 14). Applying a binary reference, BD-p-Tau217 achieved both a specificity and sensitivity of 92%, with PPV and NPV of 86% and 96%, respectively. BD-p-Tau217-derived high-risk group exhibited faster cognitive decline than the low-risk group.
CONCLUSIONS: Risk stratification for PET Aβ+ based on plasma BD-p-Tau217 suggests superior diagnostic and prognostic utility, warranting further validation.
CITATION:
Joyce R. Chong ; Saima Hilal ; Narayanaswamy Venketasubramanian ; Michael Schöll ; Nicholas J. Ashton ; Henrik Zetterberg ; Christopher P. Chen ; Mitchell K.P. Lai (2025): Plasma brain-derived p-Tau217 outperforms other p-Tau species in detecting abnormal brain amyloid in an Asian cohort of older people with cerebrovascular disease burden. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100615
CLASS-LEVEL AGGREGATION OBSCURES CLINICALLY RELEVANT HETEROGENEITY IN ANTI-AMYLOID ANTIBODY TRIALS: COMMENTS ON A COCHRANE REVIEW BY INDIVIDUAL MEMBERS OF THE EADC
Kristian Steen Frederiksen, Mercè Boada, Lutz Frölich, Milica Kramberger, Nikolaos Scarmeas, Everard Vijverberg, Pieter Jelle Visser, Gunhild Waldemar, Eric Westman, Henrik Zetterberg, Sebastiaan Engelborghs, Frank Jessen
J Prev Alz Dis 2026;7(13)
Show summaryHide summary
CITATION:
Kristian Steen Frederiksen ; Mercè Boada ; Lutz Frölich ; Milica Kramberger ; Nikolaos Scarmeas ; Everard Vijverberg ; Pieter Jelle Visser ; Gunhild Waldemar ; Eric Westman ; Henrik Zetterberg ; Sebastiaan Engelborghs ; Frank Jessen (2025): Class-level aggregation obscures clinically relevant heterogeneity in anti-amyloid antibody trials: comments on a Cochrane review by individual members of the EADC. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100598
REDUCTIONS IN NEUROPSYCHIATRIC SYMPTOMS AFTER LECANEMAB TREATMENT AND THEIR ASSOCIATIONS WITH IMAGING MARKERS OF Β-AMYLOID CLEARANCE
Yaping Yan, Daoyan Hu, Linlin Kong, Kaicheng Li, Jun Su, Yingzhe Wu, Hongwei Zhan, Hong Zhang, Yidan Sun, Xiaofeng Dou, Peiyu Huang, Jiong Zhou
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryBACKGROUND: Anti–amyloid-β (Aβ) therapies can slow cognitive decline and reduce cerebral amyloid burden in Alzheimer’s disease (AD). Neuropsychiatric symptoms (NPS) are highly prevalent across the disease course and substantially contribute to disability and caregiver burden. However, whether Aβ clearance translates into improvements in NPS remains unclear.
METHODS: We enrolled 144 individuals with AD-related mild cognitive impairment or AD dementia who received intravenous lecanemab infusions. Standardized clinical rating scales, including the Neuropsychiatric Inventory, and amyloid PET were assessed at baseline (V0), 6 months (V1), and 12 months (V2). Longitudinal changes in clinical function and amyloid burden were analyzed.
RESULTS: Lecanemab treatment was associated with robust reductions in amyloid PET biomarkers and significant short-term reductions in NPS scores in patients who completed follow-up. Longitudinal analyses showed that reductions in total NPI scores were significantly associated with amyloid-β clearance in the insular cortex. Reductions in the hyperactivity subsyndrome were associated with amyloid reduction across a broader network, including the frontal and temporal lobes, striatum, and insular cortex.
CONCLUSIONS: In this real-world cohort, lecanemab was associated with short-term reductions in NPS. Changes in NPS severity were linked to regional amyloid-β clearance.
CITATION:
Yaping Yan ; Daoyan Hu ; Linlin Kong ; Kaicheng Li ; Jun Su ; Yingzhe Wu ; Hongwei Zhan ; Hong Zhang ; Yidan Sun ; Xiaofeng Dou ; Peiyu Huang ; Jiong Zhou (2025): Reductions in neuropsychiatric symptoms after lecanemab treatment and their associations with imaging markers of β-amyloid clearance. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100600
ADAPTING THE SPANISH HEALTHCARE SYSTEM FOR DISEASE-MODIFYING TREATMENTS IN EARLY-STAGE ALZHEIMER’S DISEASE
R. Sánchez Valle, A. Lleó Bisa, A. Villarejo Galende, E. Cuartero Rodríguez, J. Escudero-Torrella, N. Bargallo Alabart
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryBACKGROUND: The emergence of disease-modifying therapies targeting amyloid pathology represents a major paradigm shift in the management of Alzheimer disease (AD). However, their implementation poses substantial organizational, infrastructural, and clinical challenges for health systems.
OBJECTIVES: To identify the key challenges and establish priority recommendations for the effective incorporation of amyloid-targeting therapies into the Spanish National Health System.
DESIGN, SETTING, AND PARTICIPANTS: This multiphase consensus study was conducted within the Spanish National Health System between September 2024 and July 2025. The study comprised a narrative literature review, qualitative research, regional workshops, and a modified RAND/UCLA Delphi process. A total of 56 experts participated, including a scientific committee of 6 Alzheimer disease specialists and an expert panel of 50 multidisciplinary professionals involved in AD care.
MEASUREMENTS: Identification of key challenges across the AD care pathway; development, evaluation, and prioritization of consensus-based recommendations; and estimation of patient demand, including projected increases in day hospital activity and magnetic resonance imaging utilization.
RESULTS: Ten key challenge areas were identified, encompassing early detection and referral, diagnostic confirmation, assessment of patient eligibility, treatment administration in day hospitals, monitoring of amyloid-related imaging abnormalities, evaluation of treatment effectiveness, infrastructure and capacity, professional training, patient information and support, and health care planning. Of the 43 recommendations assessed, 38 were rated as appropriate and necessary, with 14 prioritized for immediate implementation. Demand estimation models indicated that 11 to 26 patients per 100,000 inhabitants could be treated under current care patterns, increasing to 17 to 115 per 100,000 inhabitants under alternative eligibility scenarios.
CONCLUSIONS: This consensus defines the clinical, organizational, and infrastructural requirements necessary to integrate amyloid-targeting therapies into routine care within the Spanish National Health System. The prioritized recommendations define immediate actions to address the challenges identified and may serve as a reference for other health systems facing similar implementation processes.
CITATION:
R. Sánchez Valle ; A. Lleó Bisa ; A. Villarejo Galende ; E. Cuartero Rodríguez ; J. Escudero-Torrella ; N. Bargallo Alabart (2025): Adapting the spanish healthcare system for disease-modifying treatments in early-stage alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100586
DIAGNOSTIC PERFORMANCE OF AN AUTOMATED PLASMA P-TAU217 CHEMILUMINESCENT ASSAY FOR DETECTING AΒ PATHOLOGY IN A CHINESE MEMORY CLINIC COHORT
Shuai Chen, Feng-Yu Wang, Rong Li, Chang Fu, Jing-Yu Shao, Yu Shen, Kai Ma, Xiao-Di Hao, Lin Cao, Jun-Ling Xu, Jie-Wen Zhang
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryBACKGROUND: Blood-based biomarkers have emerged as promising tools for detecting Alzheimer’s disease (AD) pathology, but validation of automated plasma assays in Chinese clinical populations remains limited. This study evaluated the diagnostic performance of a fully automated chemiluminescent plasma biomarker assay for detecting amyloid-β (Aβ) pathology in a Chinese memory clinic cohort under different pre-analytical conditions.
METHODS: We enrolled 409 cognitively impaired participants from a single-center memory clinic, using amyloid-β positron emission tomography (Aβ-PET) as the reference standard. Plasma samples were analyzed under two pre-analytical conditions: frozen batch-processed samples from a historical cohort (n = 198) and freshly collected samples analyzed in real time in a prospective cohort (n = 211). Additionally, 95 participants underwent tau-PET imaging. Six plasma biomarkers were quantified using the Vazyme® AD Assay.
RESULTS: Across cohorts, p-tau217, p-tau217/Aβ42 ratio, and NfL/p-tau217 ratio consistently achieved excellent diagnostic performance (AUCs 0.92–0.95), followed by p-tau181 (AUCs 0.86–0.90). GFAP (AUCs 0.82–0.83) and the Aβ42/40 ratio (AUCs 0.76–0.81) showed moderate discriminative performance. Plasma p-tau217 alone achieved diagnostic accuracy comparable to composite biomarker models. A dual cut-point strategy reduced the indeterminate zone to <30%, with positive predictive values of 0.97–0.99 and negative predictive values of 0.86–0.87. Plasma p-tau217 was also significantly associated with tau-PET burden in both meta-temporal and neocortical regions (P < 0.001).
CONCLUSION: This automated chemiluminescent plasma biomarker assay demonstrated high diagnostic accuracy for detecting Aβ pathology in a Chinese memory clinic cohort under different pre-analytical conditions. The findings support its potential utility as a practical blood-based biomarker approach in specialized clinical settings, while further multicenter studies are needed to confirm its generalizability across broader populations and healthcare environments.
CITATION:
Shuai Chen ; Feng-Yu Wang ; Rong Li ; Chang Fu ; Jing-Yu Shao ; Yu Shen ; Kai Ma ; Xiao-Di Hao ; Lin Cao ; Jun-Ling Xu ; Jie-Wen Zhang (2025): Diagnostic performance of an automated plasma p-tau217 chemiluminescent assay for detecting Aβ pathology in a Chinese memory clinic cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100613
MULTIMODAL BIOMARKER CHARACTERIZATION OF AMNESTIC OBJECTIVE SUBTLE COGNITIVE DECLINE IN AGING AND PRECLINICAL ALZHEIMER’S DISEASE
David López-Martos, Raffaele Cacciaglia, Marc Suárez-Calvet, Gemma Salvadó, Mahnaz Shekari, Armand González-Escalante, Marta Milà-Alomà, Anna Brugulat-Serrat, Carolina Minguillon, Matteo Tonietto, Edilio Borroni, Gregory Klein, Clara Quijano-Rubio, Gwendlyn Kollmorgen, Henrik Zetterberg, Kaj Blennow, Juan Domingo Gispert, Oriol Grau-Rivera, Gonzalo Sánchez-Benavides, ALFA study
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryBACKGROUND: The objective of this study was to provide a multimodal biomarker characterization of amnestic objective subtle cognitive decline (obj-SCD) in aging and preclinical Alzheimer’s disease (AD).
METHODS: Prospective observational study; data from the Alzheimer’s and Families+ (ALFAs+) cohort, including cognitively unimpaired (CU) individuals with available baseline CSF biomarkers (normal or AD continuum profiles) and longitudinal neuropsychological assessment (2 time points, 3-year follow-up). Amnestic obj-SCD was defined using robust longitudinal neuropsychological references with multivariate base rate thresholds of significant decline (Free and Cued Selective Reminding Test, Memory Binding Test, Wechsler Memory Scale IV: Logical Memory). Study outcomes included plasma p-tau217, NfL, and GFAP; CSF p-tau181/Aβ42, NfL, and GFAP; Aβ and tau PET; and MRI Grey Matter volume (GMv). The associations of amnestic obj-SCD with fluid (plasma and CSF) and neuroimaging biomarkers (PET and GMv) were evaluated using mixed-effects and voxel-wise linear regression models, respectively.
RESULTS: 350 CU individuals were included (mean age 61 years; 60% female; mean education 14 years; 35% CSF Aβ-positive). Amnestic obj-SCD was identified in 10% of the sample, associated with greater AD pathology (higher plasma p-tau217, CSF p-tau181/Aβ42, global Aβ PET, medial temporal tau PET), neurodegeneration (higher plasma and CSF NfL, reduced GMv in cingulate cortex, longitudinal GMv reductions in hippocampus) and inflammation (higher plasma and CSF GFAP, longitudinal GMv increases in neocortical brain regions).
DISCUSSION: These findings highlight the need for standardized clinical staging criteria to enhance early detection and risk stratification in aging and preclinical AD.
CITATION:
David López-Martos ; Raffaele Cacciaglia ; Marc Suárez-Calvet ; Gemma Salvadó ; Mahnaz Shekari ; Armand González-Escalante ; Marta Milà-Alomà ; Anna Brugulat-Serrat ; Carolina Minguillon ; Matteo Tonietto ; Edilio Borroni ; Gregory Klein ; Clara Quijano-Rubio ; Gwendlyn Kollmorgen ; Henrik Zetterberg ; Kaj Blennow ; Juan Domingo Gispert ; Oriol Grau-Rivera ; Gonzalo Sánchez-Benavides ; ALFA study (2025): Multimodal biomarker characterization of amnestic objective subtle cognitive decline in aging and preclinical Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100612
BIOMARKERS IN PRECLINICAL AND EARLY ALZHEIMER’S DISEASE IN CHINA: A SCOPING REVIEW
Guoping Peng, Yan Yang, Ying Wang, Sagar Anil Chandekar, Jintai Yu
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryThis scoping review synthesizes evidence on fluid and neuroimaging biomarkers for preclinical and early Alzheimer’s disease (AD)—including mild cognitive impairment (MCI) and mild AD dementia—in Chinese populations, where a comprehensive overview has been lacking despite AD's increasing biomarker-based definition. We systematically searched four English databases (PubMed, EMBASE, Cochrane, and Web of Science) and three Chinese databases (CNKI, Wanfang, and CQVIP) for studies (2013–2023) reporting diagnostic accuracy of these biomarkers in Chinese preclinical and early AD (eAD) cohorts for clinical use. Due to rapid advancements in biomarker research in China, a supplementary search was conducted in the four English databases for studies published between 2024 and April 30, 2025. Of the 366 included studies investigating fluid or neuroimaging biomarkers in AD, 48 specifically evaluated biomarker performance in biomarker‑confirmed AD populations. Plasma p-tau217 showed strong performance for diagnosing MCI due to AD, and plasma p-tau217, p-tau181/Aβ42, and p-tau217/Aβ42 effectively classified amyloid-β (Aβ) pathology. Multimodal combinations and MRI-based biomarkers also performed well, though evidence is limited. In China, biomarker diagnosis of MCI due to AD is advancing rapidly, while approaches for preclinical AD, machine learning, and multi-protein panels remain in early development.
CITATION:
Guoping Peng ; Yan Yang ; Ying Wang ; Sagar Anil Chandekar ; Jintai Yu (2025): Biomarkers in preclinical and early Alzheimer’s disease in China: a scoping review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100599
ASSOCIATION BETWEEN OBSTRUCTIVE SLEEP APNEA SEVERITY AND GLYMPHATIC-RELATED DTI-ALPS ALTERATIONS IN NEWLY DIAGNOSED, DRUG-NAÏVE ALZHEIMER’S DISEASE
Wenxue Zheng, Yao Zhou, Yurui Xia, Yiqing Wang
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryBACKGROUND: Obstructive sleep apnea (OSA) is highly prevalent in Alzheimer's disease (AD) patients and is associated with cognitive decline. However, the mechanisms linking OSA to Alzheimer’s pathophysiology, especially regarding glymphatic function, remain unclear. This study investigated the relationship between OSA severity and glymphatic-related diffusion abnormalities, as assessed by the DTI-ALPS index, in newly diagnosed, drug-naïve AD patients.
METHODS: A total of 162 newly diagnosed, drug-naïve AD patients and 98 healthy controls were enrolled. Polysomnography (PSG) was used to assess OSA severity and sleep parameters, while diffusion tensor imaging along the perivascular space (DTI-ALPS) was employed to measure glymphatic function. Correlation analyses, multivariable regression models with interaction terms, and sensitivity analyses were performed to explore the relationship between OSA and glymphatic dysfunction, and whether this relationship was specific to AD.
RESULTS: In AD patients, greater OSA severity was associated with lower ALPS-index values, including AHI (rho = −0.38, P < 0.001) and ODI (rho = −0.35, P < 0.001), whereas these associations were not observed in healthy controls. Lower ALPS-index values were also associated with more fragmented sleep, including higher N1 proportion and arousal index, and with reduced REM sleep. Clinically, the ALPS-index was positively correlated with better cognitive performance on MMSE (rho = 0.28, P = 0.001) and MoCA (rho = 0.31, P < 0.001), and negatively correlated with greater cognitive impairment on ADAS-Cog (rho = −0.34, P < 0.001).
CONCLUSION: Glymphatic dysfunction is related to OSA severity in de novo AD but not in Healthy controls. The study demonstrated that OSA may contribute to neurodegeneration via glymphatic impairment in AD.
CITATION:
Wenxue Zheng ; Yao Zhou ; Yurui Xia ; Yiqing Wang (2025): Association between obstructive sleep apnea severity and glymphatic-related DTI-ALPS alterations in newly diagnosed, Drug-Naïve Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100597
VIRTUAL REALITY-BASED TRAINING IN PATIENTS WITH ALZHEIMER\'S DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS
Junjie Wang, Can Wu, Kedong Zhu, Xiaoshan Qi, Guiqin Chen
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryBACKGROUND AND OBJECTIVES: Prior meta-analyses have suggested that training utilizing virtual reality (VR) serves as a secure and effective intervention for elderly individuals experiencing mild cognitive impairment (MCI). Nevertheless, the effectiveness of such interventions appears to differ among various populations and cognitive domains. Furthermore, there remains a significant gap in understanding the effectiveness of VR-based training, specifically among individuals diagnosed with Alzheimer's disease (AD).
METHODS: The researchers conducted a comprehensive search of databases, including Web of Science, PubMed, Cochrane Library, and EMBASE up until July 1, 2025, focusing on randomized controlled trials that investigated VR-based training in patients diagnosed with AD. The outcomes measured were categorized and analyzed separately, encompassing overall cognitive performance, distinct cognitive domains, psychosocial function, physical capabilities, and the execution of daily living activities within the context of AD trials.
RESULTS: Of the 265 publications identified, 11 (4.15%) randomized controlled trials (RCTs) eventually met all eligibility criteria. Those who received VR-based training showed significantly better global cognitive function [SMD (95%CI) = 0.44 (0.21–0.68)] and Short-term memory [SMD (95%CI) = 0.62 (0.25–0.99)] than the controls. However, no significant improvements were observed in areas such as executive function, spatial memory, activities of daily living, quality of life, balance and coordination, fear of falling, risk of falls, and depression levels.
CONCLUSION: VR-based interventions demonstrated beneficial effects on global cognitive function and short-term memory in AD populations. Due to the small sample size, the current research on evidence for efficacy in people with AD is weak and limited in many indicators.
CITATION:
Junjie Wang ; Can Wu ; Kedong Zhu ; Xiaoshan Qi ; Guiqin Chen (2025): Virtual reality-based training in patients with alzheimer's disease: A systematic review and meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100590
PHENOTYPING OF MILD BEHAVIORAL IMPAIRMENT DOMAINS IN MULTI-REGIONAL DEMENTIA-FREE OLDER ADULTS OF CHINESE ETHNICITY: IMPULSE DYSCONTROL AS THE LEADING DOMAIN
Yingqi Liao, Yaping Zhang, Haoran Zhang, Yan Li, Dylan X. Guan, Yifan Yan, Yuek Ling Chai, Mitchell K.P. Lai, Shifu Xiao, Christopher L.H. Chen, Xin Xu
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryBACKGROUND: Mild behavioral impairment (MBI) is an early neurobehavioral marker of dementia, yet MBI domain patterns remain underexplored among populations of Chinese ethnicity. This study aimed to characterize MBI domain phenotypes by examining the prevalence of MBI domains and identifying the leading domain across multi-regional cohorts of dementia-free older adults of Chinese ethnicity.
METHODS: Data from three previously unpublished datasets (Hangzhou community cohort, China Longitudinal Aging Study and Singapore memory clinic cohort) and three published studies were integrated to estimate the MBI domain prevalence, measured by the Neuropsychiatric Inventory (NPI) and/or MBI-Checklist (MBI-C), through a random-effects meta-analysis. Within the Hangzhou cohort, cross-instrument consistency was evaluated. Exploratory analyses were performed in the Singapore cohort on associations between MBI domains and incident dementia.
RESULTS: Among 1817 participants, impulse dyscontrol was the most prevalent MBI domain, followed by affective dysregulation and decreased motivation, consistently across instruments and cognitive status. In the exploratory longitudinal analyses, impulse dyscontrol was associated with a greater likelihood of incident dementia (HR = 5.05, 95%CI = 2.92 – 8.73).
CONCLUSIONS: Impulse dyscontrol was the leading MBI domain among older adults of Chinese ethnicity, with potential clinical relevance for early identification and dementia risk stratification.
CITATION:
Yingqi Liao ; Yaping Zhang ; Haoran Zhang ; Yan Li ; Dylan X. Guan ; Yifan Yan ; Yuek Ling Chai ; Mitchell K.P. Lai ; Shifu Xiao ; Christopher L.H. Chen ; Xin Xu (2025): Phenotyping of mild behavioral impairment domains in multi-regional dementia-free older adults of Chinese ethnicity: impulse dyscontrol as the leading domain. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100589
INCOME, DIET, AND COGNITIVE FUNCTION: OBSERVATIONAL ANALYSES AND CANDIDATE METABOLOMIC PATHWAYS IDENTIFIED BY MENDELIAN RANDOMIZATION
Xingguang Zhao, Weijian Wu, Qiaoxuan Zhang, Mengqian Ouyang, Haoyu Luo, Qun Yu, Yingren Mai, Zhiyu Cao, Shaoqing Yang, Mingsong Xu, Jun Liu, Wang Liao
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryBACKGROUND: Household income has been shown to have impact on cognitive function, with dietary patterns and gut microbiota–related metabolic pathways potentially acting as mediating pathways. Our study integrates observational analyses and Mendelian randomization (MR) to explore these associations.
METHODS: The observational analysis included 13,457 participants from the UK Biobank who experienced cognitive transitions. A multistate Markov model was applied to assess the effect of income level on cognitive trajectory, while mediation analysis and quantile regression were performed using baseline data. We applied a two-sample, two-step MR approach utilizing genetic instruments from the IEU Open genome-wide association studies (GWAS) project to determine the causal effects of income on cognition, and further estimate the mediating roles of dietary patterns and 1400 gut metabolites linking income with cognitive performance.
RESULTS: Over a median follow-up of 8.96 years, a total of 14,040 cognitive transitions were recorded (7429 deterioration events and 6801 improvements), with higher income associated with a lower risk of cognitive deterioration. MR analyses confirmed a causal relationship between income and cognitive performance (OR: 2.140, 95% CI: 1.923–2.381; P < 0.001). Notably, cheese and coffee intake demonstrated significant mediation effects in both observational and two-way, two-step MR. The protective effect of cheese appeared to be mediated by gut metabolites, particularly via tryptophan/tyrosine and carnitine/ergothioneine.
CONCLUSIONS: Our findings indicate a significant link between income and cognitive performance, cheese and dried fruit may mediate this protective effect through amino acid and carnitine metabolism pathways. Interventions targeting dietary patterns have the potential to prevent cognitive decline attributable to low income.
CITATION:
Xingguang Zhao ; Weijian Wu ; Qiaoxuan Zhang ; Mengqian Ouyang ; Haoyu Luo ; Qun Yu ; Yingren Mai ; Zhiyu Cao ; Shaoqing Yang ; Mingsong Xu ; Jun Liu ; Wang Liao (2025): Income, diet, and cognitive function: observational analyses and candidate metabolomic pathways identified by Mendelian randomization. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100582
THE GROWING BURDEN OF DEMENTIA IN ASIA: COMPARATIVE INSIGHTS FROM JAPAN, CHINA, AND INDIA
Chen Zhang, Xuhui Chen, Yongan Sun
J Prev Alz Dis 2026;7(13)
Show summaryHide summaryBACKGROUND: Alzheimer's disease and other dementias (ADODs) are increasingly becoming a major public health concern in rapidly ageing Asia. We compared the disease burden across Japan, China, and India at different demographic stages.
DESIGN: The Global Burden of Disease Study of 2023 was used to analyze the incidence, prevalence, mortality, and disability-adjusted life years (DALYs) in 1990–2023. Decomposition analysis identified drivers of DALYs trends. DALYs associated risk factors were quantified. The Auto-Regressive Integrated Moving Average model was used to predict future disease burden.
RESULTS: In 2023, China had the highest absolute burden, with age-standardized incidence and prevalence rates of 156.63 (95% uncertainty interval [UI]: 136.58–175.49) and 918.83(95% UI: 784.59–1,058.24) per 100,000, respectively. Japan recorded the highest age-standardized mortality rate (31.25 [8.47–71.42] per 100,000). India had the highest annual increase in mortality and DALYs, with estimated annual percentage changes of 0.91 (95% confidence interval [95% CI] 0.80–1.03) and 0.51 (0.45–0.56), respectively. Decomposition analysis revealed distinct drivers: Japan was dominated by epidemiological changes; China was driven by both aging and epidemiological changes; India was mainly due to population growth and epidemiological changes. Ambient particulate matter was the leading risk factor across all countries, though India faced a unique household air pollution burden. DALYs are predicted to increase in all three countries significantly by 2038.
CONCLUSIONS: The ADODs burden remains substantial, driven by distinct demographic and epidemiological factors in Japan, China, and India. Tailored strategies for prevention and management are essential to address the growing burden.
CITATION:
Chen Zhang ; Xuhui Chen ; Yongan Sun (2025): The growing burden of dementia in Asia: Comparative insights from Japan, China, and India. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100614
LETTER TO THE EDITOR: ASIA’S DEMENTIA BURDEN: FROM EPIDEMIOLOGICAL DESCRIPTION TO PREVENTION-ORIENTED NEUROLOGY
Haoyang Hu
J Prev Alz Dis 2026;7(13)
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CITATION:
Haoyang Hu (2026): Letter to the Editor: Asia’s dementia burden: from epidemiological description to prevention-oriented neurology. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100627
LETTER TO THE EDITOR: CLARITY AD OPEN-LABEL EXTENSION DATA DO NOT ROBUSTLY CONFIRM DISEASE COURSE MODIFICATION BY LECANEMAB IN APOE4 HETEROZYGOTES AND NON-CARRIERS
Jemma Hazan, Kathy Y. Liu, Robert Howard
J Prev Alz Dis 2026;7(13)
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CITATION:
Jemma Hazan ; Kathy Y. Liu ; Robert Howard (2025): Letter to the Editor: Clarity AD open-label extension data do not robustly confirm disease course modification by lecanemab in ApoE4 heterozygotes and non-carriers. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100587
LETTER TO THE EDITOR: CLARITY AD OPEN-LABEL EXTENSION DATA DO NOT ROBUSTLY CONFIRM DISEASE COURSE MODIFICATION BY LECANEMAB IN APOE4 HETEROZYGOTES AND NON-CARRIERS
Lutz Froelich
J Prev Alz Dis 2026;7(13)
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CITATION:
Lutz Froelich (2025): Letter to the editor: Clarity AD open-label extension data do not robustly confirm disease course modification by lecanemab in ApoE4 heterozygotes and non-carriers. # TJPAD-D-26-00165. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100588
EDITORIAL: WELCOME TO CTAD25 IN SAN DIEGO!
Paul Aisen
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CITATION:
Paul Aisen (2026): Editorial: Welcome to CTAD25 in San Diego!. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100616
18TH CONFERENCE CLINICAL TRIALS ALZHEIMER’S DISEASE DECEMBER 1-4, 2025, SAN DIEGO, CA (UNITED STATES) - CONFERENCE PROCEEDINGS
SYMPOSIA, ORAL COMMUNICATIONS
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https://doi.org/10.1016/j.tjpad.2026.100617
OPEN ACCESS18TH CONFERENCE CLINICAL TRIALS ALZHEIMER’S DISEASE DECEMBER 1-4, 2025, SAN DIEGO, CA (UNITED STATES) - CONFERENCE PROCEEDINGS
POSTERS
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https://doi.org/10.1016/j.tjpad.2026.100618
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