Ahead of print articles
EVALUATION OF PLASMA P-TAU217 BIOMARKERS IN DETECTING AMYLOID PATHOLOGY AND PREDICTING COGNITIVE OUTCOMES: OBSERVATIONS FROM JAPANESE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE COHORT
Kensaku Kasuga, Masataka Kikuchi, Emiko Kikkawa-Saito, Tamao Tsukie, Takanobu Ishiguro, Akinori Miyashita, Takeshi Iwatsubo, the Japanese Alzheimer’s Disease Neuroimaging Initiative, Takeshi Ikeuchi
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BACKGROUND AND OBJECTIVES: Plasma phosphorylated tau 217 (p-tau217) has shown strong potential as a blood-based biomarker for detecting amyloid pathology in Alzheimer’s disease. This study evaluated the diagnostic and prognostic utility of plasma biomarkers, including p-tau217, in participants from the Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI) cohort.
METHODS: We analyzed paired plasma and CSF samples from 172 J-ADNI participants. CSF and plasma biomarkers were quantified using the LUMIPULSE platform, and the same plasma samples were analyzed using the Simoa platform. The diagnostic accuracy for detecting amyloid pathology and the prognostic value of plasma p-tau217 biomarkers were assessed. Associations between plasma p-tau217 and polygenic risk scores (PRS), as well as potential confounding factors, were examined.
RESULTS: Plasma p-tau217 levels measured using Lumipulse and Simoa assays were highly correlated (p < 0.001). All plasma p-tau217 assays showed high diagnostic accuracy for CSF Aβ42/Aβ40-defined amyloid pathology (AUC = 0.98). A single cutoff point based on the Youden index for p-tau217 and p-tau217/Aβ42 achieved >90% specificity and >90% sensitivity. The predefined FDA-approved two-cutoff model for p-tau217/Aβ42 was applicable to this cohort. PRS was significantly associated with plasma p-tau217 independently of APOE genotypes. Subjects with higher plasma p-tau217 levels showed a significantly increased risk of conversion to dementia and larger longitudinal cognitive declines. Plasma p-tau217 levels were significantly influenced by the body mass index, estimated glomerular filtration rate, and high-density lipoprotein cholesterol.
CONCLUSIONS: Plasma p-tau217 and p-tau217/Aβ42 are robust biomarkers for AD diagnosis and prognosis in the Japanese population.
CITATION:
Kensaku Kasuga ; Masataka Kikuchi ; Emiko Kikkawa-Saito ; Tamao Tsukie ; Takanobu Ishiguro ; Akinori Miyashita ; Takeshi Iwatsubo ; the Japanese Alzheimer’s Disease Neuroimaging Initiative ; Takeshi Ikeuchi (2026): Evaluation of plasma p-tau217 biomarkers in detecting amyloid pathology and predicting cognitive outcomes: Observations from Japanese Alzheimer’s disease neuroimaging initiative cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100502
DIGITAL MEMORY ASSESSMENTS AND PLASMA PTAU217 ENABLE EFFICIENT PRECLINICAL ALZHEIMER’S TRIALS
Casey R. Vanderlip, Daniel L. Gillen, Joshua D. Grill, Craig E.L. Stark
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BACKGROUND: Preclinical Alzheimer’s disease (AD) trials enroll cognitively unimpaired, amyloid-positive older adults; however, most remain clinically stable over typical trial durations. Limited near-term decline reduces statistical power and drives large sample sizes and high costs. Scalable enrichment strategies capable of identifying individuals most likely to decline are critically needed.
OBJECTIVES: To determine whether a brief digital memory assessment (DMA) and plasma phosphorylated tau 217 (pTau217), individually or combined, identify preclinical AD participants at elevated risk for cognitive and biological progression, and whether such enrichment reduces clinical trial sample-size requirements.
DESIGN: Analysis of data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) Study, a multicenter randomized clinical trial with 240 weeks of follow-up.
SETTING: Secondary-prevention trial conducted across sites in the United States, Canada, Australia, and Japan.
PARTICIPANTS: A total of 1,169 cognitively unimpaired adults aged 65–85 years who were amyloid-positive and completed both a baseline DMA and plasma pTau217 measurement.
MEASUREMENTS: Primary outcome was change in the Preclinical Alzheimer Cognitive Composite (PACC) over 240 weeks. Secondary outcomes included Clinical Dementia Rating–Sum of Boxes, Mini-Mental State Examination, Cognitive Function Instrument, and annualized change in amyloid PET, plasma pTau217, and tau PET.
RESULTS: Participants with both elevated pTau217 and low DMA exhibited the greatest cognitive decline and reached the 240-week PACC decline of the overall cohort 83 weeks earlier. Participants with neither marker showed minimal decline. Dual enrichment reduced sample-size estimates for a clinical trial from 3,252 to 818 participants per arm (75 % reduction). These individuals also demonstrated faster increases in plasma pTau217 and neocortical tau PET.
CONCLUSIONS: A brief DMA combined with plasma pTau217 identifies a subset of cognitively unimpaired, amyloid-positive older adults at highest risk for cognitive and biomarker progression. This dual-marker enrichment strategy enables smaller, shorter, and more cost-efficient preclinical AD trials and supports more targeted evaluation of preventive therapies.
CITATION:
Casey R. Vanderlip ; Daniel L. Gillen ; Joshua D. Grill ; Craig E.L. Stark (2026): Digital memory assessments and plasma pTau217 enable efficient preclinical Alzheimer’s trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100503
SPATIAL AMYLOID–INFORMED MULTIMODAL BRAIN AGE AS AN EARLY MARKER OF ALZHEIMER’S-RELATED VULNERABILITY AND RISK STRATIFICATION
Liang Cui, Qing-Min Wang, Zhen Zhang, Min Wang, You-Yi Tu, Jie-Hui Jiang, Yi-Hui Guan, Yue-Hua Li, Fang Xie, Qi-Hao Guo
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BACKGROUND: Brain age gap (BAG)—the difference between predicted and chronological age—captures neurobiological aging, but MRI-only models insufficiently reflect Alzheimer’s disease (AD) pathology. Whether incorporating regional amyloid-β (Aβ) positron emission tomography (PET) improves sensitivity to early AD processes remains unknown.
OBJECTIVES: To develop an amyloid-informed multimodal BAG model and examine its associations with cognition, plasma biomarkers, and functional connectivity across the AD continuum.
DESIGN: Cross-sectional analysis using integrated machine-learning models.
SETTING: Chinese Preclinical Alzheimer’s Disease Study (CPAS), a cohort recruited from community settings and memory clinics.
PARTICIPANTS: Nine hundred ninety community-dwelling adults spanning normal cognition, subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia.
MEASUREMENTS: Regional Aβ-PET and structural MRI informed BAG estimation. Cognitive tests, plasma biomarkers (p-tau217, p-tau181, neurofilament light [NfL], glial fibrillary acidic protein [GFAP], Aβ42/40), and hippocampus–default mode network (DMN) connectivity from resting-state fMRI were assessed.
RESULTS: Higher BAG was associated with greater odds of SCD, MCI, or dementia across the cohort, with stronger effects in Aβ-positive individuals. BAG explained more cognitive variance than global Aβ burden and was linked to multidomain cognitive deficits. Elevated BAG corresponded to higher p-tau217, p-tau181, NfL, and GFAP and lower Aβ42/40, indicating early biomarker alterations. BAG was also associated with reduced hippocampus–DMN connectivity.
CONCLUSIONS: An amyloid-informed multimodal BAG model captures convergent AD-related pathology, biomarker alterations, and cognitive vulnerability beyond amyloid burden alone, supporting its value for individualized risk s2tratification and prevention-focused assessment.
CITATION:
Liang Cui ; Qing-Min Wang ; Zhen Zhang ; Min Wang ; You-Yi Tu ; Jie-Hui Jiang ; Yi-Hui Guan ; Yue-Hua Li ; Fang Xie ; Qi-Hao Guo (2025): Spatial amyloid–informed multimodal brain age as an early marker of Alzheimer’s-related vulnerability and risk stratification. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100501
CUMULATIVE BLOOD PRESSURE AND RISK OF DEMENTIA AND COGNITIVE DECLINE: A SYSTEMATIC REVIEW AND META-ANALYSIS
Ruirui Wang, Yijie Gao, Nicole Ee, Fope Akinyede, Xiaoyue Xu, Linan Chen, Shangzhi Xiong, Xiaoying Chen, Craig S. Anderson, Katie Harris, Ruth Peters
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BACKGROUND AND OBJECTIVE: Cumulative blood pressure (cBP), reflecting long-term BP exposure, is increasingly used to examine risk associations with dementia and cognitive function, but findings to date are inconsistent. This systematic review aimed to synthesize existing evidence to clarify risk associations in adults.
METHODS: We searched for articles in Medline, Embase (Ovid), Web of Science, Cochrane Library, and China National Knowledge Infrastructure from inception to January 2025 in any language. Longitudinal, observational studies involving participants aged over 18 years at the time of initial BP assessment were eligible for inclusion. cBP was defined as the area under the curve of BP values over time or an equivalent method, expressed in units of mmHg × time. Study outcomes were dementia, cognitive function assessments, and neuroimaging markers. This review is registered in PROSPERO (CRD42025640637).
RESULTS: From 6334 records identified, 10 independent prospective cohort studies from 9 publications were included in the review, of which four cohort studies were eligible for meta-analysis. Meta-analysis showed that higher cumulative systolic BP (cSBP) was associated with an increased risk of incident dementia (odds ratio [OR] 1.21, 95% CI 1.00–1.45; I² = 92.4%, P for heterogeneity<0.001), while cumulative diastolic BP (cDBP) was not associated with dementia risk (OR 0.97, 95% CI 0.72–1.32; I²=97.3%, P for heterogeneity<0.001). Among eight studies on cognitive function, five reported that higher cSBP was associated with poorer cognitive performance, while three reported non-significant results. In contrast, findings for higher cDBP were mixed, with two studies reporting adverse associations, two reporting protective associations, and three reporting null associations. Two studies linked higher cSBP and cDBP to greater white matter hyperintensity burden. Sensitivity and subgroup analyses suggested that the positive association between cSBP and dementia-related outcomes were more pronounced among middle-aged adults, whereas inverse or null associations for higher cDBP was observed in some cohorts among individuals aged ≥60 years.
CONCLUSION: Higher cSBP is associated with increased risk of incident dementia and cognitive decline, whereas associations for cDBP are mixed. Given the limited evidence, future studies should incorporate age-stratified analyses and consider including cumulative pulse pressure and mean arterial pressure to further clarify the relationship between cBP and cognition.
CITATION:
Ruirui Wang ; Yijie Gao ; Nicole Ee ; Fope Akinyede ; Xiaoyue Xu ; Linan Chen ; Shangzhi Xiong ; Xiaoying Chen ; Craig S. Anderson ; Katie Harris ; Ruth Peters (2025): Cumulative blood pressure and risk of dementia and cognitive decline: a systematic review and meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100500
LETTER TO THE EDITOR: REFLECTIONS ON THE ROLE OF AI IN ALZHEIMER’S DISEASE RESEARCH: ADDRESSING INCLUSIVITY, CAUSALITY, AND ETHICAL CONSIDERATIONS
Mingyue Chen, Yan Han
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CITATION:
Mingyue Chen ; Yan Han (2026): Letter to the Editor: Reflections on the role of AI in Alzheimer’s disease research: Addressing inclusivity, causality, and ethical considerations. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100488
PRECLINICAL AMYLOID PATHOLOGY IS ASSOCIATED WITH ANXIETY BUT NOT DEPRESSION IN COGNITIVELY NORMAL OLDER ADULTS: EVIDENCE FOR DIFFERENTIAL NEUROPSYCHIATRIC PATHWAYS
Jonathan Vogelgsang, Clara Beck, Regan Patrick, Ipsit Vahia, Sara Weisenbach
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INTRODUCTION: Neuropsychiatric symptoms may represent early Alzheimer's disease (AD) manifestations, but their relationship with amyloid pathology in cognitively unimpaired individuals remains unclear.
METHODS: We analyzed 4,492 cognitively unimpaired adults (aged 65-85) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Study. Participants completed amyloid-PET imaging and assessments of anxiety, depression, memory complaints, and AD concerns.
RESULTS: 1,231 participants (27.4%) were amyloid-positive. While anxiety and depression scores remained within normal ranges, amyloid-positive participants reported higher memory complaints (p = 0.008) and AD concerns (p < 0.001) before status disclosure. Regression analyses showed amyloid burden associated with anxiety (β = 0.04, standardized, p = 0.003) but not depression (p = 0.68). Mediation analyses revealed anxiety was directly associated with amyloid, while depression was mediated through subjective cognitive concerns.
DISCUSSION: Preclinical amyloid pathology directly associates with subclinical anxiety but only indirectly with depression through subjective stress, suggesting distinct neuropsychiatric pathways in early AD that could inform detection strategies.
CITATION:
Jonathan Vogelgsang ; Clara Beck ; Regan Patrick ; Ipsit Vahia ; Sara Weisenbach (2026): Preclinical amyloid pathology is associated with anxiety but not depression in cognitively normal older adults: Evidence for differential neuropsychiatric pathways. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100497
TRAJECTORIES OF SOCIAL PARTICIPATION AND RISK OF COGNITIVE IMPAIRMENT IN CHINESE OLDER ADULTS: A SIX-YEAR LONGITUDINAL STUDY
Kangle Wang, Ruihan Wan, Jiale Peng, Huanghao Zhou, Kaifeng Xu, Hao Liu, Lidian Chen, Zhizhen Liu
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BACKGROUND: The growing burden of cognitive decline represents a significant public health concern in aging populations, particularly in China. Social participation is a modifiable factor that may protect against cognitive decline, yet its long-term dynamic association with cognitive impairment remains insufficiently characterized.
OBJECTIVES: This study aimed to delineate long-term trajectories of social participation and determine their association with cognitive impairment in Chinese older adults.
DESING: Longitudinal cohort study.
SETTING: The study utilized data collected in 2013, 2015, and 2018 from the China Health and Retirement Longitudinal Study.
PARTICIPANTS: We included 3074 Chinese adults aged ≥60 years who were free of cognitive impairment in 2013, had complete social participation data in 2013/2015/2018, and completed cognitive assessments in 2018
INTERVENTION(S): Not applicable.
MEASUREMENTS: Social participation was derived from CHARLS self-reported activity items and frequency and summed into a composite score (range 0–33). Cognitive performance was assessed using episodic memory (immediate and delayed 10-word recall) and mental status (orientation, serial subtraction, and figure drawing), yielding a global score (range 0–31); cognitive impairment was defined as a score <11. Group-based trajectory modeling identified five social participation trajectories. Multivariable logistic regression estimated odds ratios (ORs) for cognitive impairment adjusting for sociodemographic, health, and behavioral covariates.
RESULTS: Five distinct social participation trajectories were identified. In the fully adjusted model, relative to the “stable low” group, those in the “low baseline–increasing” (OR = 0.66, 95% CI: 0.47–0.92), “stable intermediate” (OR = 0.75, 95% CI: 0.58–0.97), and “stable high” (OR = 0.41, 95% CI: 0.22–0.76) groups had markedly reduced chances of cognitive impairment, while no significant link was found for the “moderate decline” group (OR = 0.90, 95% CI: 0.71–1.17).
CONCLUSIONS: Maintaining or increasing one’s social activities was linked to a notably lower likelihood of cognitive decline. These results highlight the importance of social involvement patterns as a modifiable factor for fostering cognitive strength. Interventions to maintain or enhance participation are therefore a viable strategy for the primary prevention of cognitive decline in older adults.
CITATION:
Kangle Wang ; Ruihan Wan ; Jiale Peng ; Huanghao Zhou ; Kaifeng Xu ; Hao Liu ; Lidian Chen ; Zhizhen Liu (2026): Trajectories of social participation and risk of cognitive impairment in Chinese older adults: A six-year longitudinal study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100499
EXPERIMENTAL AND TRANSLATIONAL MODELS OF ALZHEIMER’S DISEASE: FROM NEURODEGENERATION TO NOVEL THERAPEUTIC INSIGHTS
Nadeemullah Khan, Somnath De, Suhasini Boddu, Navya Pravala
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Neurodegeneration on demand represents a groundbreaking approach to modeling Alzheimer’s disease (AD) in animals, enabling precise study of its molecular and behavioral hallmarks. Novel techniques, including optogenetic activation of amyloidogenic pathways, viral vector-mediated delivery of mutated human genes (e.g., APP, MAPT), and synthetic tau fibril analogs, induce AD-like pathology, including amyloid-beta plaques, tau hyperphosphorylation, neuroinflammation, and synaptic loss in diverse species, ranging from transgenic rodents to cephalopods and cannies. Emerging platforms, such as bioengineered neural organoids grafted into immunocompromised hosts, allowed for the controlled onset of AD-like features, providing unique insights into disease progression. Advanced tools like real-time neuroimaging and single-cell multi-omics help elucidate the temporal and cellular dynamics of neurodegeneration. These models provided unparalleled opportunities to dissect AD’s complex mechanisms, including protein misfolding, glial dysregulation, and cognitive decline. However, challenges remained, including interspecies molecular disparities, incomplete replication of human AD complexity, and ethical concerns surrounding cognitive impairment in sentient models. This review explores these innovative strategies, their contributions to understanding AD’s pathogenesis, and their potential to accelerate the development of transformative therapies, while also addressing limitations and future directions for refining these pioneering models.
CITATION:
Nadeemullah Khan ; Somnath De ; Suhasini Boddu ; Navya Pravala (2026): Experimental and translational models of Alzheimer’s disease: From neurodegeneration to novel therapeutic insights. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100498
ASSOCIATION OF CARDIAC BIOMARKERS WITH LONGITUDINAL COGNITIVE CHANGES IN THE GENERAL POPULATION
Fang-Fei Wei, Dubo Chen, Chaoxin Xu, Zhongping Yu, Zihao Chen, Chang Chen, Xin He, JingJing Zhao, Wenqing Li, Cuiping Zhao, Jiangui He, Yugang Dong, Jan A. Staessen, Chen Liu
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BACKGROUND: Little is known about the association of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) with changes in cognitive performance over time.
OBJECTIVES: To investigate the association of cardiac biomarkers with cognitive changes over time.
PARTICIPANTS: The study population consisted of 2540 stroke-free participants (56.1 % women; 21.2 % Black; mean age, 74.5 years) enrolled in the Atherosclerosis Risk in Communities study.
MEASUREMENTS: Associations of the changes in the Mini Mental State Examination (MMSE) scores with the log-transformed cardiac biomarkers were modelled using multivariable linear and restricted cubic spline regression.
RESULTS: Over 6.6 years (median), the MMSE score decreased by 0.57 (95 % CI, 0.46–0.67) and the frequency of an MMSE score <24 increased from 5.339 % to 9.69 % (P < 0.001). In multivariable-adjusted models, the cardiac biomarkers measured at baseline were linearly related to absolute MMSE changes with association sizes amounting to 0.47 (0.27–0.66) and 0.58 (0.19–0.97) for NT-proBNP and hs-cTnT, respectively. Classification-by-cardiac biomarker interactions were significant for race, age group and diabetes in relation to NT-proBNP (P ≤ 0.031) and for race, age group and hypertension in relation to hs-cTnT (P ≤ 0.041). For both biomarkers, associations were stronger in Blacks than Whites and in older than younger individuals; for NT-proBNP in diabetic than non-diabetic participants; and for hs-cTnT in normotensive than hypertensive individuals.
CONCLUSION: NT-proBNP and hs-cTnT were associated with MMSE changes. Although association studies cannot prove causality, the clinical implication might be that targeting the heart within the framework of a multifactorial approach might be strategy in reducing cognitive decline.
CITATION:
Fang-Fei Wei ; Dubo Chen ; Chaoxin Xu ; Zhongping Yu ; Zihao Chen ; Chang Chen ; Xin He ; JingJing Zhao ; Wenqing Li ; Cuiping Zhao ; Jiangui He ; Yugang Dong ; Jan A. Staessen ; Chen Liu (2026): Association of cardiac biomarkers with longitudinal cognitive changes in the general population. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100494
LETTER TO THE EDITOR : RE-THINKING FUNDING SUCCESS IN ALZHEIMER’S DISEASE RESEARCH: WHY GOOD SCIENCE IS NOT ENOUGH
Peter Fusdahl, Miguel G. Borda, Dag Aarsland
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CITATION:
Peter Fusdahl ; Miguel G. Borda ; Dag Aarsland (2026): Long-term fasting insulin variability and cognitive function: Insights from tRe-thinking funding success in Alzheimer’s disease research: Why good science is not enoughhe CARDIA study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100496
LONG-TERM FASTING INSULIN VARIABILITY AND COGNITIVE FUNCTION: INSIGHTS FROM THE CARDIA STUDY
Bo-Shui Huang, Zuo-Yu Huang, Yu-Hong Zeng, Kun-Hao Bai, Jing-Bin Guo, Jun Weng, Ze-Hua Li, Qing-Yun Hao
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BACKGROUND AND AIM: Fasting insulin variability has emerged as a potential marker of metabolic dysregulation, but its long-term implications for cognitive function remain unclear. This study aimed to clarify the role of long-term fasting insulin variability in predicting individual cognitive function risk.
METHODS: We analyzed data from CARDIA study participants who underwent cognitive testing and had at least three insulin measurements. Fasting insulin was measured at 7 timepoints over 30 years. Intra-individual insulin variability was assessed using standard deviation (SD), coefficient of variation (CV), and average real variability (ARV). Cognitive function was evaluated using the Digit Symbol Substitution Test (DSST), Stroop Test, and Rey Auditory Verbal Learning Test (RAVLT), with results standardized to z-scores and combined into a global cognitive z-score. Multivariable linear models were used to assess associations with cognitive performance.
RESULTS: In the 25-year analysis (n = 2712), higher long-term insulin variability was significantly associated with poorer global cognitive performance at year 25 after adjustment for demographic, lifestyle, and cardiometabolic covariates (CV-insulin: β=–0.719; 95% CI: –1.161 to –0.276; P < 0.01; SD-insulin: β=–0.019; 95% CI: –0.036 to –0.002; P < 0.05). These associations remained significant after additional adjustment for either concurrent insulin at year 25 or mean insulin levels over 25 years. Domain-specific analyses showed that higher insulin variability was associated with lower DSST z-scores (worse attention) and higher Stroop interference z-scores (worse executive function). Extended analyses over 30 years (n = 2069) yielded consistent results: higher CV-insulin was inversely associated with global cognitive z-scores (β=–0.837; 95% CI: –1.347 to –0.327), as well as with DSST (β=–0.347; 95% CI: –0.581 to –0.112) and RAVLT z-scores (β=–0.276; 95% CI: –0.522 to –0.031). These associations persisted after full adjustment for year 30 covariates and time-varying confounders across the follow-up, supporting the temporal robustness and clinical relevance of insulin variability as an independent predictor of cognitive function.
CONCLUSIONS: Greater long-term insulin variability is independently associated with poorer midlife cognitive performance. These findings highlight insulin variability as a potential marker of cognitive health risk.
CITATION:
Bo-Shui Huang ; Zuo-Yu Huang ; Yu-Hong Zeng ; Kun-Hao Bai ; Jing-Bin Guo ; Jun Weng ; Ze-Hua Li ; Qing-Yun Hao (2026): Long-term fasting insulin variability and cognitive function: Insights from the CARDIA study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100487
POTENTIAL ROLE OF MRI TO OPTIMIZE CLINICAL TRIAL DESIGN FOR PROGRESSIVE SUPRANUCLEAR PALSY AND CORTICOBASAL DEGENERATION
Jesús García-Castro, Lawren VandeVrede, Michael C. Donohue, Lídia Vaqué-Alcázar, Sara Rubio-Guerra, Judit Selma-González, Hilary W. Heuer, Alejandra O. Morcillo-Nieto, María Franquesa, Oriol Dols-Icardo, Alexandre Bejanin, Olivia Belbin, Juan Fortea, Daniel Alcolea, Maria Carmona-Iragui, Carla Abdelnour, Isabel Barroeta, Miguel Santos-Santos, María Belen Sánchez Saudinós, Isabel Sala, Alberto Lleó, Maria Luisa Gorno-Tempini, Maria Luisa Mandelli, Rema Raman, Anne-Marie A Wills, Eden Barragan, Irene Litvan, Brad Boeve, Brad Dickerson, Murray Grossman, Edward D. Huey, David J. Irwin, Alex Pantelyat, Carmela Tartaglia, Julio C. Rojas, Adam L. Boxer, Ignacio Illán-Gala, on behalf of theFour Repeat Tau Neuroimaging Initiative (4RTNI) and the AL108-231 Investigators
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BACKGROUND: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are 4–repeat tauopathies (4RT) presenting with overlapping syndromes. Imperfect clinicopathological associations increase sample-size demands in clinical trials. We test whether MRI can enrich trials for PSP/CBD and provide sensitive MRI-based outcome measures.
METHODS: Longitudinal cohort analysis including participants from the 4 Repeat Tauopathy Neuroimaging Initiative (4RTNI) and phase 2/3 Davunetide trial (DAV). An MRI model trained on autopsy-confirmed cases predicted PSP (MRI-PSP) or CBD (MRI-CBD); corticobasal syndrome (CBS) with positive Alzheimer’s biomarkers was reclassified. Clinical scales and MRI-derived thickness/volume were analyzed with linear mixed-effects models. We derived data-driven MRI-signatures (optimal regional combinations) to minimize required trial sample sizes.
RESULTS: 206 participants from 4RTNI (n = 106 with Richardson’s syndrome [RS], CBS, or nonfluent/agrammatic primary progressive aphasia [nfvPPA]) and DAV (n = 100 with RS). In 4RTNI, 49 participants were predicted MRI-PSP and 43 MRI-CBD. 76% of MRI-PSP had RS, 24% had CBS/nfvPPA; 66% of MRI-CBD had CBS. PSP and CBD signatures shared midbrain/pontine atrophy but differed in cortical involvement. PSP signature correlated strongly with 12-month change on the PSP Rating Scale (β = –0.59, p < 0.001). MRI-based signatures reduced the estimated sample sizes required to detect 30% reduction in progression over 12-months by 50% for MRI-PSP and 87% for MRI-CBD, compared with clinical outcomes. In DAV, feasibility was replicated.
CONCLUSION: MRI-derived models can identify PSP or CBD with high accuracy, and MRI-based signatures track progression more sensitively than established clinical outcomes. Incorporating these tools into therapeutic trial design could reduce sample sizes and enable more inclusive disease-modifying trials for 4RT.
CITATION:
Jesús García-Castro ; Lawren VandeVrede ; Michael C. Donohue ; Lídia Vaqué-Alcázar ; Sara Rubio-Guerra ; Judit Selma-González ; Hilary W. Heuer ; Alejandra O. Morcillo-Nieto ; María Franquesa ; Oriol Dols-Icardo ; Alexandre Bejanin ; Olivia Belbin ; Juan Fortea ; Daniel Alcolea ; Maria Carmona-Iragui ; Carla Abdelnour ; Isabel Barroeta ; Miguel Santos-Santos ; María Belen Sánchez Saudinós ; Isabel Sala ; Alberto Lleó ; Maria Luisa Gorno-Tempini ; Maria Luisa Mandelli ; Rema Raman ; Anne-Marie A Wills ; Eden Barragan ; Irene Litvan ; Brad Boeve ; Brad Dickerson ; Murray Grossman ; Edward D. Huey ; David J. Irwin ; Alex Pantelyat ; Carmela Tartaglia ; Julio C. Rojas ; Adam L. Boxer ; Ignacio Illán-Gala ; on behalf of theFour Repeat Tau Neuroimaging Initiative (4RTNI) and the AL108-231 Investigators (2026): Potential role of MRI to optimize clinical trial design for progressive supranuclear palsy and corticobasal degeneration. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100486
LECANEMAB OVER A TWO-YEAR DURATION: KEY INSIGHTS FROM A REGIONAL SPECIALTY MEDICAL CENTER
Lisa B.E. Shields, Hust Hannah, Gregory E. Cooper, Theresa Kluthe, Rachel N. Hart, Andrew P. Thaliath, Brandon C. Dennis, Stephanie W. Freeman, Jessica F. Cain, Whoy Y. Shang, Kendall M. Wasz, Adam T. Orr, Christopher B. Shields, Shirish S. Barve, Kenneth G. Pugh
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BACKGROUND AND OBJECTIVES: The anti-amyloid monoclonal antibody lecanemab (Leqembi®) treats patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease (AD). We sought to evaluate the incidence of amyloid-related imaging abnormalities) ARIA and other adverse events associated with lecanemab.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective and observational study features 187 patients who received at least one lecanemab infusion at our multidisciplinary Norton Neuroscience Institute Memory Center over a two-year duration (August 25, 2023-August 24, 2025).
RESULTS: A total of 109 (58.3 %) patients were diagnosed with MCI, and 78 (41.7 %) had mild dementia prior to starting lecanemab. The mean age at the initial infusion was 73 years (Range: 49-90 years). Most (127 [67.9 %]) patients were female, and the majority (181 [96.8 %]) were Caucasian. Of the 175 patients who underwent at least one surveillance brain MRI following lecanemab initiation, 39 (22.3 %) had evidence of ARIA (both ARIA-H and ARIA-E: 13 [33.3 %]; solitary ARIA-H: 17 [43.6 %]; and solitary ARIA-E: 9 [23.1 %]). Of these 39 patients, 20 (51.3 %) were ε4 heterozygous, 12 (30.8 %) were ε4 homozygous, and 7 (17.9 %) were ε4 non-carriers. Patients who were ε4 homozygous more frequently had evidence of any ARIA (p-value = 0.002), ARIA-E (p = 0.041), and ARIA-H (p = 0.004). Of the 25 patients who underwent at least one surveillance brain MRI and were ε4 homozygous, 12 (48.0 %) had ARIA detected. Five (12.8 %) patients with ARIA were symptomatic, requiring lecanemab suspension. Three of these symptomatic patients were ε4 homozygous, and two were ε4 heterozygous. The ARIA was most frequently detected on the surveillance brain MRI performed before the 5th infusion (29 [74.4 %] patients). All 39 cases of ARIA occurred before the 14th lecanemab infusion. Patients with more baseline microbleeds more frequently developed any ARIA (ARIA-H and ARIA-E) (p = 0.041) and solitary ARIA-H (p = 0.022). The presence of baseline microbleeds was associated with a higher frequency of solitary ARIA-H, though was only marginally statistically significant (p = 0.051). Sixty (32.1 %) patients experienced infusion-related adverse effects, with 54 (90.0 %) occurring after the first lecanemab infusion. Mild and transient headaches were most common, affecting 26 (48.1 %) of these patients after the first infusion. After initiating a pre-infusion oral cocktail of acetaminophen 650 mg, loratadine 10 mg, and famotidine 20 mg, the number of patients who experienced an infusion-related adverse event decreased from 45.2 % to 28.3 %. Thirty-two (17.1 %) patients discontinued lecanemab, primarily due to cognitive decline associated with progressive AD (10 [31.2 %]) and ARIA progression (9 [28.1 %]). Of the 73 patients who had MMSE scores performed at baseline and after 1 year post-lecanemab, 13 (17.8 %) had increased scores, 51 (69.9 %) had decreased scores, and the scores remained the same in 9 (12.3 %) patients.
CONCLUSIONS: Our findings suggest that ARIA is a significant concern especially in patients who are ε4 homozygous. Close monitoring of patients who are ε4 carriers is recommended to recognize any complications that may ensue.
CITATION:
Lisa B.E. Shields ; Hust Hannah ; Gregory E. Cooper ; Theresa Kluthe ; Rachel N. Hart ; Andrew P. Thaliath ; Brandon C. Dennis ; Stephanie W. Freeman ; Jessica F. Cain ; Whoy Y. Shang ; Kendall M. Wasz ; Adam T. Orr ; Christopher B. Shields ; Shirish S. Barve ; Kenneth G. Pugh (2026): Lecanemab over a two-year duration: Key insights from a regional specialty medical center. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100489
THE INFLUENCE OF BAPINEUZUMAB AND SEMAGACESTAT ON RAPID PROGRESSORS: A RETROSPECTIVE COHORT STUDY
Kristofer Harris, Madison Shyer, Dulin Wang, Elizabeth He, Matias Cattani, Catherine Zhang, Christine M. Farrell, Xiaoqian Jiang, Yejin Kim, Paul E. Schulz
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BACKGROUND: A subset of Alzheimer's disease patients progresses much more rapidly than average. These rapid progressors exhibit accelerated cognitive and functional decline. Potential differences in Alzheimer’s biomarkers for rapid progressors and their responses to disease-modifying treatments remain poorly understood, with previous clinical trials and studies producing limited biomarker data and inconsistent results.
OBJECTIVES: Examine differences in rapid progressor versus non-rapid progressor outcomes in two AD treatment trials (bapineuzumab and semagacestat) and investigate cognitive and biomarker progression in the placebo groups.
DESIGN: Retrospective cohort study.
SETTING: Four randomized, double-blind, phase 3 clinical trials from the Center for Global Clinical Research Data (Semagacestat) and the Yale University Open Data Access Project (Bapineuzumab).
PARTICIPANTS: 4,902 patients (2,355 in bapineuzumab trials, 2,647 in semagacestat trials). Rapid progressors were operationally defined as the 10% of patients with the largest changes in cognitive scores from baseline to trial end.
INTERVENTION: Bapineuzumab (monoclonal antibody) and Semagacestat (γ-secretase inhibitor).
MEASUREMENTS: Cognitive assessments (CDR-SB, MMSE, ADAS-Cog, ADCS-ADL) and biological markers (CSF and plasma levels, MRI, FDG PET Scan, and Amyloid PET Scan) at baseline and endpoint.
RESULTS: Rapid progressors showed distinct baseline characteristics in both the bapineuzumab and semagacestat trials: younger age (61.27 vs 63.14 years, p=0.008; and, 72.64 v. 73.64 years, p=0.046), a higher proportion of APOE4 carriers (87.6% vs 41.4%, p<0.001; and, 85.2% vs 49.3%, p = 0.022), and greater cognitive impairment across all measures (p<0.001). Both progression groups demonstrated improvement in specific biomarkers with treatment, though with different patterns. With bapineuzumab according to Conditional Average Treatment Effect analysis, rapid progressors showed biomarker improvement in amyloid CSF, p-Tau CSF, and amyloid PET scan, while non-rapid progressors demonstrated biomarker improvements in p-Tau CSF, amyloid PET, and MRI. With semagacestat, rapid progressors showed improvements in amyloid CSF and plasma while non-rapid progressors showed improvements in amyloid CSF, FDG PET, and MRI.
CONCLUSIONS: This study provides crucial insights for clinical practice and trial design. The distinct response patterns between progression groups suggest that early identification and balancing of RPs between groups could improve clinical trial efficiency. The findings support the development of personalized treatment approaches for rapid progressors, who have aggressive disease progression. These results may significantly modify clinical trial design and patient care in Alzheimer’s disease.
CITATION:
Kristofer Harris ; Madison Shyer ; Dulin Wang ; Elizabeth He ; Matias Cattani ; Catherine Zhang ; Christine M. Farrell ; Xiaoqian Jiang ; Yejin Kim ; Paul E. Schulz (2026): The influence of bapineuzumab and semagacestat on rapid progressors: A retrospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100483
NO LONGITUDINAL ASSOCIATION BETWEEN HEARING LOSS AND ALZHEIMER’S DISEASE PATHOLOGY
Jordi H.C. Boons, Phuong Thuy Nguyen Ho, Anna van Houwelingen, M. Arfan Ikram, Gertjan Dingemanse, Bernd Kremer, Meike W. Vernooij, Andre Goedegebure, Julia Neitzel
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INTRODUCTION: Hearing loss (HL) is a potential risk factor for Alzheimer’s disease (AD), with animal studies suggesting a bidirectional relationship. This study examines whether HL links to changes in AD pathology and, whether AD biomarkers relate to subsequent HL progression.
MEHODS: Baseline Aβ42/Aβ40 and p-tau217 were measured using single-molecule arrays in 474 participants of the Rotterdam Study (mean age=62.37) between 2010-2016. HL was defined as the better-ear’s pure-tone threshold average. After seven years, participants underwent amyloid PET; HL and p-tau217 were reassessed two years after PET.
RESULTS: Baseline HL was not associated with amyloid PET positivity, Aβ42/Aβ40, or longitudinally with p-tau217. Likewise, HL progression did not predict PET outcomes. APOE4 carriership did not modify associations with Aβ PET. Similarly, baseline plasma biomarkers were also unrelated to longitudinal HL changes.
CONCLUSION: No bidirectional association was observed between HL and AD pathology, suggesting that HL may contribute to dementia through other pathways.
CITATION:
Jordi H.C. Boons ; Phuong Thuy Nguyen Ho ; Anna van Houwelingen ; Arfan Ikram ; Gertjan Dingemanse ; Bernd Kremer ; Meike W. Vernooij ; Andre Goedegebure ; Julia Neitzel (2026): No longitudinal association between hearing loss and Alzheimer’s disease pathology. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100481
CLINICAL, IMAGING AND BLOOD BIOMARKER OUTCOMES IN A PHASE 3 CLINICAL TRIAL OF TAU AGGREGATION INHIBITOR HYDROMETHYLTHIONINE MESYLATE IN MILD COGNITIVE IMPAIRMENT AND MILD TO MODERATE DEMENTIA DUE TO ALZHEIMER’S DISEASE
Claude M Wischik, Richard Stefanacci, Peter Bentham, Serge Gauthier, Henrik Zetterberg, Gordon K Wilcock, Lutz Froelich, Alistair Burns, Emer MacSweeney, Clive Ballard, Jin-Tai Yu, Tay Siew Choon, Vahe Asvatourian, Natalia Muehlemann, Jan Priel, Karin Kook, Tenecia Sullivan, Diane Downie, Sonya Miller, Carol Pringle, John M. D Storey, Tom Baddeley, Charles R Harrington, Lewis K Penny, Mohammad Arastoo, Roger Staff, Anca-Larisa Sandu, Helen Shiells, Serena Lo, Nafeesa Nazlee, Emily Evans, Claire Hull, Bjoern O Schelter
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BACKGROUND: Hydromethylthionine mesylate (HMTM) targets tau pathology and has tau-independent symptomatic activity.
OBJECTIVES: To evaluate the safety and efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer’s disease (AD).
SETTING: 82 centres in Canada, European Union, United Kingdom and United States of America.
PARTICIPANTS: A total of 598 amyloid β-PET positive participants were included; 44% (263) met clinical criteria for MCI due to Alzheimer’s disease and 56% (335) were diagnosed with mild to moderate dementia due to AD. Intervention: HMTM 16 mg/day and 8 mg/day were compared with methylthioninium chloride (MTC) 4 mg twice weekly, intended as an inactive urinary colourant to preserve blinding with respect to possible urinary discolouration caused by HMTM.
MEASUREMENTS: HMTM and MTC were compared on cognitive and functional endpoints for the first 52 weeks followed by all receiving HMTM 16 mg/day to 104 weeks in a modified delayed-start trial design. Biomarker outcomes included change in plasma levels of neurofilament light chain (NfL), pTau217 and MRI measures of grey matter atrophy.
RESULTS: It was not possible to demonstrate significant differences on the co-primary clinical endpoints (ADAS-cog11 and ADCS-ADL23) at 52 weeks due to symptomatic activity in the control arm. In participants with MCI, statistically significant differences in cognitive decline (ADAS-cog13) emerged at 78 weeks (p = 0·0291) and 104 weeks (p = 0·0308) between early- and delayed-start HMTM 16 mg/day in analyses specified prior to the 24-month database lock. Statistically significant cognitive improvement over baseline score was sustained for 78 weeks in the early start MCI group, with no significant cognitive or functional decline to 104 weeks. There was a significant reduction in progression of neurodegeneration measured by NfL change (p = 0·0291) at 52 weeks in the whole population, consistent with significant reductions in progression of grey matter atrophy at 52 and 104 weeks, and a reduction in progression of tau pathology (pTau217, p = 0·0165) in MCI. Headache (1·5%) and diarrhoea (1·2%) were the most frequent adverse effects.
CONCLUSIONS: Although HMTM 16 mg/day arrested progression of neurodegeneration and reduced grey matter atrophy at 52 weeks, symptomatic activity in the control arm precluded separation of treatment arms at 52 weeks on primary clinical endpoints. In participants with MCI, significant clinical separation was seen only at 78 and 104 weeks. This effect has been confirmed in a further study. HMTM was well tolerated and has the potential to offer an accessible oral treatment option with a benign safety profile which could be delivered with minimal patient/physician burden.
CITATION:
Claude M Wischik ; Richard Stefanacci ; Peter Bentham ; Serge Gauthier ; Henrik Zetterberg ; Gordon K Wilcock ; Lutz Froelich ; Alistair Burns ; Emer MacSweeney ; Clive Ballard ; Jin-Tai Yu ; Tay Siew Choon ; Vahe Asvatourian ; Natalia Muehlemann ; Jan Priel ; Karin Kook ; Tenecia Sullivan ; Diane Downie ; Sonya Miller ; Carol Pringle ; John M. D Storey ; Tom Baddeley ; Charles R Harrington ; Lewis K Penny ; Mohammad Arastoo ; Roger Staff ; Anca-Larisa Sandu ; Helen Shiells ; Serena Lo ; Nafeesa Nazlee ; Emily Evans ; Claire Hull ; Bjoern O Schelter (2026): Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100480
CEREBRAL HAEMODYNAMICS AND WHITE MATTER HYPERINTENSITIES: FINDINGS USING NON-INVASIVE BRAIN IMAGING
Ashwati Vipin, James Xiao Yuan Chen, Mervin Tee, Saima Hilal, Yi Jin Leow, Simon Konstandin, Klaus Eickel, Matthias Günther, Jan Petr, Henk JMM Mutsaerts, Nagaendran Kandiah
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BACKGROUND: Utilizing non-invasive neuroimaging for characterization of blood brain barrier (BBB) changes and perfusion deficits underlying small vessel disease pathobiology including white matter hyperintensities (WMH) remains largely unexplored.
OBJECTIVES: We examined the underlying haemodynamics of WMH by assessing complex relationships between cerebral blood flow, BBB permeability and WMH burden.
DESIGN, SETTING, PARTICIPANTS: Cross-sectional data from study participants belonging to the community-based Biomarker and Cognition Cohort Study, Singapore was obtained.
MEASUREMENTS: Brain structural and novel non-invasive multi-echo Arterial Spin Labeling data was obtained from 128 participants to derive cerebral blood flow (CBF), arterial transit time (ATT) and BBB time of exchange (Tex).
RESULTS: Neurovascular measures from BBB imaging comprising lower CBF (β=-0.005; p = 0.0139), longer ATT (β=0.644; p = 0.0132) and shorter BBB Tex (β=-0.002; p = 0.0023) were independently associated with higher WMH and higher age-at-visit. Model fit statistics indicated good fit for the structural equation model with a comparative fit index of 0.975 and Standardized Root Mean Square Residual of 0.074. Structural equation modelling revealed CBF (β=0.533; p < 0.001) and ATT (β=-0.254; p = 0.001) as predictors of BBB permeability. Subsequently higher BBB permeability predicted higher WMH burden (β=-0.387; p < 0.001). Additionally, vascular risk factors comprising higher blood pressure and haemoglobinA1C related to lower CBF and shorter BBB Tex.
CONCLUSIONS: Our study highlights that CBF and ATT contribute to BBB permeability, which in turn impacts WMH burden. Vascular risk factors also impact neurovascular measures. These findings add to the growing evidence on the potential role of BBB and perfusion deficits underlying small vessel disease burden.
CITATION:
Ashwati Vipin ; James Xiao Yuan Chen ; Mervin Tee ; Saima Hilal ; Yi Jin Leow ; Simon Konstandin ; Klaus Eickel ; Matthias Günther ; Jan Petr ; Henk JMM Mutsaerts ; Nagaendran Kandiah (2026): Cerebral haemodynamics and white matter hyperintensities: findings using non-invasive brain imaging. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100479
A REGIONAL FRAMEWORK FOR THE DETECTION AND MANAGEMENT OF ARIA WITH ANTI-AMYLOID THERAPIES IN EARLY ALZHEIMER’S DISEASE IN ASIA
So Young Moon, Ta-Fu Chen, Bo-Ching Lee, Won Jin Moon, Nagaendran Kandiah, Sumeet Kumar, Young Ho Park, Kaori Inaba, Amitabh Dash
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Alzheimer’s disease (AD) is a growing public health concern in Asia, with an increasing prevalence driven by demographic shifts and rising life expectancy. The introduction of anti-amyloid monoclonal antibodies such as lecanemab and donanemab marks a pivotal transition from symptomatic management of AD to disease-modifying approaches, but their clinical use requires careful monitoring for amyloid-related imaging abnormalities (ARIA), a key safety consideration that presents either as vasogenic edema or as microhemorrhages and superficial siderosis. ARIA has been observed in varying frequencies across global and Asian clinical trial populations, underscoring the need for region-specific guidance. With our early clinical experiences in South Korea, Taiwan and Singapore serving as archetypes in Asia, we outline a framework for the detection and management of ARIA in Asian healthcare settings, accounting for disparities in imaging infrastructure, genetic factors, and clinician experience. Pre-treatment risk stratification, standardized imaging protocols, and severity-based treatment modifications are central to the framework, highlighting the critical role of multidisciplinary collaboration involving neurologists, geriatricians, psychiatrists, and radiologists in ensuring accurate detection and management of ARIA. Additionally, the paper highlights the role of pharmacovigilance, real-world evidence generation, physician education, and healthcare system preparedness in optimizing the safety and efficacy of anti-amyloid therapies in Asia. The proposed framework aims to ensure safe and effective use of anti-amyloid therapies while mitigating ARIA-related risks, thereby optimizing therapeutic outcomes for early AD in diverse healthcare settings across Asia.
CITATION:
So Young Moon ; Ta-Fu Chen ; Bo-Ching Lee ; Won Jin Moon ; Nagaendran Kandiah ; Sumeet Kumar ; Young Ho Park ; Kaori Inaba ; Amitabh Dash (2026): A regional framework for the detection and management of ARIA with anti-amyloid therapies in early Alzheimer’s disease in Asia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100477
PREPARING FOR THE IMPLEMENTATION OF ANTI-AMYLOID THERAPIES IN EUROPE: ASSESSING REAL-WORLD ELIGIBILITY FOR LECANEMAB AND DONANEMAB IN A SWEDISH MEMORY CLINIC
Anna Rosenberg, Alina Solomon, Alexandre Bonnard, Makrina Daniilidou, Göran Hagman, Anette Hall, Anna Matton, Ulf Öhlund-Wistbacka, Eric Westman, Miia Kivipelto
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Lecanemab and donanemab are the first anti-Aβ treatments to receive approval in Europe. Eligibility criteria are strict, eg., APOE ε4/4 carriers are excluded. Successful implementation in public healthcare hinges on accurate estimates of eligibility rates in settings which will be the first to roll out the treatments (specialized memory clinics with early disease stages). We applied the appropriate use recommendations (AUR) to assess treatment eligibility in a Swedish tertiary memory clinic where Aβ and APOE assessments are routinely performed. Of the full cohort (N = 410), 26 and 25 patients met the AUR criteria for lecanemab and donanemab, respectively (6 %; partial overlap between the groups). After excluding APOE ε4/4 carriers in line with the European guidelines, only 14 and 13 patients remained eligible (3 %). In clinics with younger populations, a significant percentage of potentially eligible patients are likely to have the APOE ε4/4 genotype. These findings are important to inform the implementation of anti-Aβ treatments.
CITATION:
Anna Rosenberg ; Alina Solomon ; Alexandre Bonnard ; Makrina Daniilidou ; Göran Hagman ; Anette Hall ; Anna Matton ; Ulf Öhlund-Wistbacka ; Eric Westman ; Miia Kivipelto (2025): Preparing for the implementation of anti-amyloid therapies in Europe: Assessing real-world eligibility for lecanemab and donanemab in a Swedish memory clinic. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100476
THE LIVER AS A METABOLIC AND IMMUNE HUB IN ALZHEIMER’S DISEASE: FROM MECHANISMS TO THERAPEUTIC OPPORTUNITIES
Jiajie Chen, Luyao Wang, Yingying Zhou, Shuoyan Zhao, Qin Chen, Kai Zheng
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Research on Alzheimer’s disease (AD) has traditionally focused on the brain. However, emerging evidence indicates that the liver acts as a silent partner in neurodegeneration. As a core hub for metabolic and immune regulation, the liver communicates bidirectionally with the brain via the liver–brain axis, participating in the regulation of various neurophysiological processes, including neurotransmitter regulation, feeding behavior, and cognition. This review summarizes how liver-derived hepatokines, inflammatory mediators, and metabolic products modulate brain function. We highlight that liver dysfunction disrupts the expression of critical molecules—including fibroblast growth factor 21, insulin-like growth factor 1, lipopolysaccharide, and lipocalin-2—thereby driving AD progression by impairing pathological protein clearance, activating neuroinflammation, exacerbating insulin resistance and oxidative stress, and disrupting lipid metabolism. We also discuss the therapeutic potential of targeting the liver–brain axis through lifestyle interventions (e.g., exercise and diet) and pharmacological approaches, to identify novel strategies to delay AD progression. In summary, we underscore the pivotal role of the liver–brain axis in AD pathogenesis and propose it as a promising target for early diagnosis and innovative therapies.
CITATION:
Jiajie Chen ; Luyao Wang ; Yingying Zhou ; Shuoyan Zhao ; Qin Chen ; Kai Zheng (2026): The liver as a metabolic and immune hub in Alzheimer’s disease: From mechanisms to therapeutic opportunities. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100478
PREECLAMPSIA AS A REVERSIBLE RISK FACTOR FOR ALZHEIMER’S DISEASE: A PROSPECTIVE MRI STUDY ON MORPHOLOGICAL CHANGES OF THE CEREBRAL CORTEX AND IMPAIRMENT OF COGNITIVE FUNCTIONS
Yuanyuan Wang, Meng Li, Tao Chen, Yanli Li, Qingqing Wang, Xinyue Zhang, Na Wang, Linfeng Yang, Lingfei Guo, Wenying Nie
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PURPOSE: To investigate the cross-sectional and longitudinal alterations in cortical thickness and surface area and Cognitive Impairment among patients with preeclampsia.
METHODS: The thickness and surface area of the cerebral cortex were systematically segmented from MRI using the automated cortical segmentation software FreeSurfer, and the corresponding values for each brain region were accurately quantified. Data collection includes the clinical characteristics, serological markers of proteins associated with cognitive function, and cognitive assessments.
RESULTS: Compared with healthy pregnancies, the cortical thicknesses of the right caudal anterior cingulate (R-CACg), right posterior cingulate (R-PoCg), right rostral anterior cingulate (R-RoACg), and right superior frontal (R-SF) in the preeclampsia group exhibited significant alterations. Notably, the change in the R-SF was specific to preeclampsia and was not associated with normal physiological pregnancies. Mediation analysis further confirmed that elevated prepregnancy BMI was directly associated with reduced Symbol Digit Modalities Test scores and indirectly contributed to cognitive decline through an increase in MAP. The cortical thickness of left pars opercularis was identified as a key component in this underlying mechanism. No statistically significant changes in cortical surface area were observed in patients with preeclampsia. Follow-up studies have indicated that cortical thickness alterations in brain regions associated with preeclampsia demonstrate signs of recovery. Among cognitive-related test indicators, only the Auditory Word Learning Test exhibited a statistically significant improvement.
CONCLUSION: The cortical thickness alterations in the R-CACg, R-PoCg, R-RoACg, and R-SF of patients with preeclampsia may represent the structural basis for cognitive impairment. Longitudinal studies have confirmed the neuroplasticity of cortical thickness changes and the potential for recovery from preeclampsia-related memory deficits.
CITATION:
Yuanyuan Wang ; Meng Li ; Tao Chen ; Yanli Li ; Qingqing Wang ; Xinyue Zhang ; Na Wang ; Linfeng Yang ; Lingfei Guo ; Wenying Nie (2025): Preeclampsia as a reversible risk factor for Alzheimer’s disease: A prospective MRI study on morphological changes of the cerebral cortex and impairment of cognitive functions. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100475
PLASMA AΒ42/AΒ40 DETERMINED BY MASS SPECTROMETRY IS ASSOCIATED WITH LONGITUDINAL CHANGES IN AMYLOID ACCUMULATION, BRAIN ATROPHY, AND CONVERSION TO MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER’S DISEASE IN INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE: 5-YEAR FOLLOW-UP OF THE FACEHBI COHORT
Noelia Fandos, María Pascual-Lucas, Leticia Sarasa, Jose Terencio, Mª Eugenia Sáez, Juan Pablo Tartari, Ángela Sanabria, Oscar Sotolongo-Grau, Amanda Cano, Lluís Tárraga, Miren Jone Gurruchaga, Agustín Ruíz, Xavier Montalban, Mercè Boada, Montserrat Alegret, Marta Marquié, José Antonio Allué, on behalf of the FACEHBI study group, on behalf of the AMYPAD consortium
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BACKGROUND: The accurate identification of individuals at risk of Alzheimer’s disease (AD) through blood-based biomarkers remains challenging.
OBJECTIVES: To evaluate the association between plasma amyloid-beta (Aβ)42/Aβ40 ratio and longitudinal amyloid deposition, clinical progression, brain atrophy and cognitive decline.
DESIGN, SETTING AND PARTICIPANTS: This study extends the Fundació ACE Healthy Brain Initiative (FACEHBI) study (Barcelona, Spain), comprising 200 individuals with subjective cognitive decline (SCD) followed over five years.
MEASUREMENTS: Aβ42/Aβ40 ratio was quantified using ABtest-MS, an antibody-free mass-spectrometry (MS) method. Survival analyses compared conversion risks to amyloid-PET positivity and mild cognitive impairment (MCI), in participants classified as low or high Aβ42/Aβ40, based on a cutoff of ≤ 0.241. Linear mixed-effect models evaluated associations of this biomarker with longitudinal changes in amyloid deposition, brain volume, and cognition.
RESULTS: Low baseline Aβ42/Aβ40 was significantly associated with increased amyloid accumulation (β = 0.257, 95% confidence interval (CI) 0.177–0.336, P < 0.001), and with higher risk of conversion to Aβ-PET positivity (Hazard ratio (HR) = 2.84, 95% CI 1.14–7.04, P = 0.025) and to MCI due to AD (HR = 3.25, 95% CI 1.17–9.01, P = 0.024). It was also linked to decreased hippocampal (β = -1.183, 95% CI -2.154 to -0.211, P = 0.017) and cortical (β = -75.921, 95% CI -151.728 to -0.113, P = 0.050) volumes, and increased ventricular volume (β = 35.175, 95% CI 18.559–51.790, P < 0.001). Moreover, lower baseline levels of Aβ42/Aβ40 were weakly associated with greater worsening in Mini-Mental State Examination and complex associative memory.
CONCLUSIONS: Our findings suggest that the plasma Aβ42/Aβ40 ratio is associated with future amyloid accumulation, brain atrophy, and conversion to prodromal AD in individuals with SCD. This biomarker may help characterize individuals with a higher likelihood of progression and could support earlier and more personalized strategies.
CITATION:
Noelia Fandos ; María Pascual-Lucas ; Leticia Sarasa ; Jose Terencio ; Mª Eugenia Sáez ; Juan Pablo Tartari ; Ángela Sanabria ; Oscar Sotolongo-Grau ; Amanda Cano ; Lluís Tárraga ; Miren Jone Gurruchaga ; Agustín Ruíz ; Xavier Montalban ; Mercè Boada ; Montserrat Alegret ; Marta Marquié ; José Antonio Allué ; on behalf of the FACEHBI study group (2025): Plasma Aβ42/Aβ40 determined by mass spectrometry is associated with longitudinal changes in amyloid accumulation, brain atrophy, and conversion to mild cognitive impairment due to Alzheimer’s disease in individuals with subjective cognitive decline: 5-year follow-up of the FACEHBI cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100465
SAFETY PROFILES OF LECANEMAB: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS AND REAL-WORLD EVIDENCE
Lin Qi, Fangxue Zheng, Mengjiao Tu, Reema Abdullah, Yilei Zhao, Xinhui Su, Dan Zhou, Guoping Peng
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BACKGROUND: Safety profiles of lecanemab, an anti-amyloid-β antibody for the treatment of early Alzheimer’s disease (AD), remain uncertain and may vary between randomized controlled trials (RCTs) and real-world evidence (RWE) studies.
OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the safety, tolerability, and acceptability of lecanemab based on findings from both RCTs and emerging RWE studies.
METHODS: We systematically searched major databases and clinical trial registries from their inception to June 2025. Random-effects meta-analyses were performed to estimate the pooled incidence of key safety outcomes, including amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation (due to ARIA, adverse events [AEs], or any cause). The risk of ARIA according to the ApoE4 genotype was assessed via relative risk (RR). This study was registered with PROSPERO (No. CRD420251110679).
RESULTS: A total of two RCTs and five RWE studies encompassing 1576 patients were included. The pooled ARIA incidence was 19% (95% CI: 16%-23%), which was significantly modulated by ApoE4 status (RR 1.45 for heterozygotes, 3.54 for homozygotes vs noncarriers) and the pooled symptomatic ARIA incidence was 3% (95% CI: 2%-4%). IRRs occurred in 26% (95% CI: 19%–34%), with heterogeneity reduced in patients receiving specific pre-infusion prophylaxis. The pooled rate of discontinuation due to AEs was 8% (95% CI: 5%-11%), with discontinuation due to ARIA occurring in 5% (95% CI: 3%-7%) of patients in RWE studies.
CONCLUSIONS: Lecanemab-related ARIA demonstrates a clear ApoE4 gene-dose effect, supporting routine ApoE4 genotyping before treatment. Standardizing pre-infusion prophylaxis may reduce variability in IRRs incidence, while prompt recognition and management of ARIA are critical for improving treatment tolerability. These findings provide important evidence to support the safe clinical use of lecanemab.
CITATION:
Lin Qi ; Fangxue Zheng ; Mengjiao Tu ; Reema Abdullah ; Yilei Zhao ; Xinhui Su ; Dan Zhou ; Guoping Peng (2025): Safety profiles of lecanemab: A systematic review and meta-analysis of randomized controlled trials and real-world evidence. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100473
ASSOCIATION BETWEEN PLASMA METAL ELEMENT PROFILES AND COGNITIVE IMPAIRMENT IN OCCUPATIONALLY ALUMINUM-EXPOSED WORKERS AT A LARGE ALUMINUM PLANT IN NORTHERN CHINA
Xin Guo, Fangyu Gao, Mujia Li, Baolong Pan, Feng Gao, Shanshan Wang, Jingsi Zhang, Xiaoting Lu, Jing Song, Linping Wang, Huifang Zhang, Qiao Niu
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This study explored the association between plasma levels of multiple metals and cognitive impairment (CI) in 455 aluminum electrolysis workers from a northern Chinese plant, divided into CI (256) and control (199) groups by MoCA scores. Using inductively coupled plasma mass spectrometry, 11 metals were measured, with analyses via conditional logistic regression,generalized linear models (GLM), Bayesian kernel machine regression (BKMR), and age stratification (40 years). Plasma aluminum (Al), lead (Pb), lithium (Li), manganese, cobalt, and copper were significantly higher in the CI group (all P < 0.05), while zinc showed no difference. Single-element analysis found Al, Pb, and Li negatively correlated with MoCA total and subscores (e.g., visuospatial function; P < 0.05), and zinc positively correlated with attention (β = 1.10, P < 0.05). BKMR confirmed metal mixtures above the 25th percentile reduced MoCA scores (β = -0.875, 95 % CI: -1.379 to -0.371), with Al, Pb, and Li as key contributors (PIP > 0.6). Subgroup analysis showed Al primarily affected those <40, while Pb had greater impact in those >40. Findings indicate elevated Al, Pb, and Li associate with higher CI risk, metal mixtures synergistically exacerbate impairment, and age modifies these effects, aiding occupational cognitive impairment prevention.
CITATION:
Xin Guo ; Fangyu Gao ; Mujia Li ; Baolong Pan ; Feng Gao ; Shanshan Wang ; Jingsi Zhang ; Xiaoting Lu ; Jing Song ; Linping Wang ; Huifang Zhang ; Qiao Niu (2025): Association between plasma metal element profiles and cognitive impairment in occupationally aluminum-exposed workers at a large aluminum plant in northern China. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100470
PHASE 3 RANDOMIZED CLINICAL TRIALS OF SIMUFILAM IN MILD-TO-MODERATE ALZHEIMER’S DISEASE
James W. Kupiec, Anton P. Porsteinsson, Raymond S. Turner, Suzanne Hendrix, Craig Mallinckrodt, Arifulla Khan, Ian Cohen, Jonathan Liss, Roger Clarnette, Kee Hyung Park, Antonio M. Hernandez, Lindsay H. Burns
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BACKGROUND: Soluble amyloid β1–42 (Aβ42) signals via the α7 nicotinic acetylcholine receptor to hyperphosphorylate tau in Alzheimer's disease (AD). Simufilam disrupts this pathogenic signaling by binding filamin A and disrupts its linkages with inflammatory receptors to reduce neuroinflammation. We assessed simufilam in two Phase 3 clinical trials in mild-to-moderate AD.
METHODS: Participants were age 50–87 with Stage 4 or 5 CE, a mini-mental state exam (MMSE) ≥16 and ≤27 and a Clinical Dementia Rating Global Score (CDR-GS) of 0.5, 1 or 2. The criterion supporting AD pathology was plasma phosphorylated (p)-tau181 or prior amyloid PET. RETHINK randomized participants to simufilam 100 mg or placebo for 52 weeks. REFOCUS evaluated simufilam 50 and 100 mg versus placebo for 76 weeks. Co-primary endpoints were change from baseline on ADAS-Cog12 and ADCS-ADL. Sub-studies assessed exploratory plasma biomarkers and, in REFOCUS only, CSF and imaging biomarkers.
RESULTS: Both trials failed to meet co-primary, secondary or exploratory biomarker endpoints. REFOCUS was terminated early, with 22% of participants still active in the trial. In the predefined mild subgroup in REFOCUS, simufilam was associated with slower cognitive decline than placebo through Week 64 (p = 0.019). This finding disappeared at Week 76 with 45% missing data and did not replicate in RETHINK. Favorable nominal exploratory post-hoc findings amongst participants with the highest half of screening plasma p-tau181 levels occurred in RETHINK but not REFOCUS. The plasma p-tau181 entry criterion did not reliably exclude amyloid PET negativity in the sub-study.
CONCLUSIONS: Simufilam did not meet co-primary or secondary endpoints in these Phase 3 trials. Simufilam was safe and well tolerated. Trials registered at clinicaltrials.gov: NCT04994483 and NCT05026177.
CITATION:
James W. Kupiec ; Anton P. Porsteinsson ; Raymond S. Turner ; Suzanne Hendrix ; Craig Mallinckrodt ; Arifulla Khan ; Ian Cohen ; Jonathan Liss ; Roger Clarnette ; Kee Hyung Park ; Antonio M. Hernandez ; Lindsay H. Burns (2025): Phase 3 randomized clinical trials of simufilam in mild-to-moderate Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100469
IDENTIFYING RISK FACTORS OF YOUNG-ONSET DEMENTIA AND EVALUATING EVIDENCE HIERARCHY: A META-ANALYSIS AND UMBRELLA REVIEW
Jiayu Zhang, Dandan Yang, Jian Liang, Yin Hu, Liping Rao, Jun Huang, Qijun Wu, Bo Jiang
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BACKGROUND: Young-onset dementia (YOD) directly affects the working-age population. The premature onset of dementia intensifies peer caregiving responsibilities and diverts medical and nursing resources. While modifiable risk factors for late-onset dementia have been well established, uncertainty remains regarding the applicability of these findings to YOD. We aim to identify modifiable risk factors for YOD and evaluate the strength of evidence.
METHODS: We searched PubMed, Embase, Web of Science, and Ovid Medline from inception to 22 May 2025 for epidemiological studies on non-genetic risk factors for YOD. We used random-effects meta-analyses with the inverse variance method to pool relative risks (RRs) and 95% confidence intervals (CIs). A series of statistical tests were designed to classify the strength of evidence of significant associations as convincing, highly suggestive, suggestive, or weak evidence.
RESULTS: From 25,731 initial and 2289 updated search records, 36 studies examining 31 non-genetic risk factors for YOD were identified. Of the 31 associations examined, 21 were nominally statistically significant at P < 0.05 based on random-effects models. Prior stroke was convincingly associated with an increased risk of YOD. Evidence of association was highly suggestive for alcohol use disorders, diabetes, depression, mood disorders, Parkinson's disease, multiple sclerosis, use of antidepressants/antipsychotics, and asthma.
CONCLUSION: We found that the risk of dementia in young individuals may be closely related to neuropsychiatric symptoms and clinical alcohol disorders. Future research should further validate these findings and explore intervention strategies to reduce dementia risk in younger individuals.
CITATION:
Jiayu Zhang ; Dandan Yang ; Jian Liang ; Yin Hu ; Liping Rao ; Jun Huang ; Qijun Wu ; Bo Jiang (2025): Identifying risk factors of young-onset dementia and evaluating evidence hierarchy: a meta-analysis and umbrella review. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100467
BRAIN HEALTH NAVIGATION IN A LARGE INTEGRATED HEALTHCARE SYSTEM
G.E. Cooper, S. Patton, D. Lockridge, S.W. Freeman, D. Drexler, K. Wasz
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Alzheimer’s Disease is a complex, chronic illness of increasing prevalence in the US and worldwide. The complexity of this illness, and its impact on caregivers make it an ideal candidate for navigation services. The development of billable navigation codes now make it possible to create a financially sustainable navigation program. We describe our initial experience with a brain health navigator program, partnering between primary and specialty memory care, in a large integrated healthcare system. While a number of challenges exist, and careful planning was required, we have successfully implemented a navigation program, enrolling greater than 100 patients in the initial 6 months. Patient and caregiver feedback has been highly positive. We have experienced no significant barriers to reimbursement and when accounting for incremental downstream revenue generation (e.g. MRI, labs), we are forecasting long-term financial sustainability and the opportunity for continued scaling over time.
CITATION:
G.E. Cooper ; S. Patton ; D. Lockridge ; S.W. Freeman ; D. Drexler ; K. Wasz (2025): Brain health navigation in a large integrated healthcare system. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100471
COST-EFFECTIVENESS ANALYSIS OF BLOOD-BASED BIOMARKER TESTING IN THE DIAGNOSIS OF ALZHEIMER’S DISEASE PATHOLOGY
Yonghong Li, Robert J. Lagier, Michael K. Racke, Yuri A. Fesko
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OBJECTIVES: We aimed to evaluate the cost-effectiveness of blood-based biomarker (BBM) testing vs amyloid positron emission tomography (PET) in patients with signs and symptoms of cognitive decline in a neurologist/specialist care setting.
METHODS: We constructed a decision-tree model to compare diagnostic outcomes and costs of two testing strategies: BBM testing with confirmatory PET scan vs PET scan alone. Their cost-effectiveness was evaluated from a payer perspective with test performance taken from a clinical study and costs including testing/imaging and physician fees.
RESULTS: When access to PET scans is unlimited, BBM triage testing would identify 98.2 % of PET+ patients with a lower average cost per diagnosis compared with PET scan alone ($8868 vs 10,345 per PET+ diagnosis). In terms of incremental cost-effectiveness, BBM triage testing would save $93,984 for each loss of PET+ diagnosis (9.1 times the average cost per PET+ diagnosis by PET scan). Under limited capacity of PET scans, more test-positive patients could be identified using BBM testing than PET scan alone. When access to PET scans is limited to 50 % of the patients, BBM testing would identify 90.6 % more test-positive patients (at 93 % sensitivity) at an incremental cost-effectiveness ratio of $3484 per gain of positive diagnosis, lower than the average cost of a PET+ diagnosis by PET scan ($10,938).
CONCLUSION: BBM testing, compared with PET scan alone, is more efficient in the utilization of available amyloid PET scans and is cost-effective for assessment of Alzheimer’s disease pathology in patients with signs and symptoms of cognitive decline.
CITATION:
Yonghong Li ; Robert J. Lagier ; Michael K. Racke ; Yuri A. Fesko (2025): Cost-effectiveness analysis of blood-based biomarker testing in the diagnosis of Alzheimer’s disease pathology. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100474
HEAD INJURY/TRAUMATIC BRAIN INJURY AND THE RISK OF DEMENTIA: AN OBSERVATIONAL AND MENDELIAN RANDOMIZATION STUDY
Ziyu Ouyang, Bin Jiao, Xuewen Xiao, Qijie Yang, Yuan Zhu, Lu Shen, Nan Li
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BACKGROUND: This study aimed to investigate the link between head injury (HI)/traumatic brain injury (TBI) and dementia risk, as it remains unclear.
METHODS: We examined the associations between HI/TBI-related factors, including the frequency of HIs and the severity of TBI, and the risk of dementia (n = 397,581), as well as neuroimaging outcomes (n = 42,380) using prospective data (50 years at baseline) from the UK Biobank. In the observational analyses, Cox proportional-hazards modeling and logistic regression were used to estimate the associations between factors. Mendelian randomization (MR) was conducted to investigate the underlying causality between TBI (n = 392,423, ncases=19,842) and Alzheimer's disease (AD) (n = 41,944, ncases=21,982).
RESULTS: During the 12.5-year follow-up period, 7524 participants developed dementia. HI and TBI conferred an increased dementia risk (hazard ratio (HR)=1.72, 95 % confidence interval (CI): 1.50–1.97; HR=1.86, 95 % CI: 1.46–2.38, respectively). The risk increased in relation to recurrent HIs (HR=4.05, 95 % CI: 2.24–7.32) or severe TBI (HR=4.50, 95 % CI: 3.18–6.37). Dementia risk was highest during the first 30 months following HI occurrence (HR=2.20, 95 % CI: 1.66–2.92), whereas there was no association after 40 years post-HI. Patients with recurrent HIs also exhibited reduced hippocampal volumes and increased white matter hyperintensity. HI was additionally associated with poorer reasoning ability and longer reaction time. Besides, the MR analysis supported a causal association between TBI and AD (odds ratio (OR)=1.17, 95 % CI: 1.01–1.37).
CONCLUSION: These results imply that HI/TBI is associated with increased dementia risk. Strategies are needed to mitigate the impact of subsequent dementia.
CITATION:
Ziyu Ouyang ; Bin Jiao ; Xuewen Xiao ; Qijie Yang ; Yuan Zhu ; Lu Shen ; Nan Li (2025): Head injury/traumatic brain injury and the risk of dementia: An observational and Mendelian randomization study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100468
JPAD Volume 13, N°02 - 2026
ASSOCIATIONS OF MODIFIABLE AND NON-MODIFIABLE RISK FACTORS WITH LONGITUDINAL WHITE MATTER HYPERINTENSITIES, AMYLOID-Β AND TAU - A PROSPECTIVE COHORT STUDY
Isabelle Glans, Niklas Mattsson-Carlgren, Olof Strandberg, Erik Stomrud, Rik Ossenkoppele, Danielle van Westen, Nicola Spotorno, Oskar Hansson, Sebastian Palmqvist
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: The global prevalence of dementia is rapidly expanding and is expected to triple by 2050. Approximately 45 % of dementia cases are estimated to be attributable to potentially modifiable risk factors. Identifying how these factors contribute to specific brain pathologies may improve strategies to reduce dementia incidence.
OBJECTIVES, DESIGN, SETTING: The aim of this study was to identify both non-modifiable and modifiable risk factors associated with longitudinal changes in white matter hyperintensities (WMH), amyloid-beta (Aβ) and tau. Data were acquired in the prospective observational Swedish BioFINDER-2 study between May 2017-January 2025. All participants underwent clinical assessments, questionnaires and at least two magnetic resonance imaging (MRI), Aβ Positron Emission Tomography (PET) and tau PET scans, respectively. Mixed-effects models were used to assess the associations between non-modifiable and modifiable risk factors and WMH (MRI), Aβ (PET) and tau (PET).
PARTICIPANTS: A total of 494 cognitively unimpaired participants were included, of whom 365 were amyloid-negative (CU Aβ−) and 129 were amyloid-positive (CU Aβ+).
MEASUREMENTS AND MAIN OUTCOMES: Non-modifiable (age, apolipoprotein E (APOE) ɛ4 genotype and sex) and modifiable risk factors (co-morbidities at baseline, such as hypertension and cardiovascular disease, BMI, and sleep duration) were analyzed with mixed-effects models, adjusted for age and sex, to predict longitudinal measurements of WMH, Aβ and tau.
RESULTS: Mean age was 64.8 (SD 13.3) years and mean follow-up was 3.9 (SD 1.5) years. Predictors represent baseline data, both predictors and outcomes are on standardized scales. Linear mixed-effects models, adjusted for age and sex, showed that higher blood pressure (β = 0.02, 95 % CI :0.01–0.02), presence of hyperlipidemia (β = 0.03, 0.01–0.05), ischemic heart disease (β = 0.06, 0.03–0.09), smoking (β = 0.02, 0.00–0.03) and lower education (β = -0.01, -0.02– -0.01) were associated with a longitudinal increase in WMH. Presence of the APOE ε4 allele was linked to faster Aβ accumulation (β = 0.03, 0.02–0.04) and tau (β = 0.01, 0.00–0.03), but only to Aβ among Aβ+ positive participants. Higher depression score (β = 0.01, 0.00–0.01) and diabetes (β = 0.02, 0.00–0.04) were associated with faster Aβ accumulation. Lower BMI was associated with faster accumulation of tau (β = -0.01, -0.02– -0.01).
CONCLUSIONS: Modifiable risk factors of future dementia primarily affect accumulation of cerebral vascular pathology, although lower BMI was associated with tau accumulation and diabetes with Aβ accumulation.
CITATION:
Isabelle Glans ; Niklas Mattsson-Carlgren ; Olof Strandberg ; Erik Stomrud ; Rik Ossenkoppele ; Danielle van Westen ; Nicola Spotorno ; Oskar Hansson ; Sebastian Palmqvist (2025): Associations of modifiable and non-modifiable risk factors with longitudinal white matter hyperintensities, amyloid-β and tau - a prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100448
ASSOCIATION OF NEIGHBORHOOD DISADVANTAGE WITH ALZHEIMER\'S DISEASE PATHOLOGY AND THE STABILITY OF BLOOD-BASED BIOMARKER PERFORMANCE
Alison Myoraku, Isabella Hausle, Marta Mila-Aloma, Pamela Thropp, Laura A. Wang, P. Murali Doraiswamy, Duygu Tosun, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: Neighborhood-level factors, measured by the Area Deprivation Index (ADI), are linked to comorbidities of Alzheimer's disease and related dementias (ADRD). However, their direct association with AD neuropathology is unclear. The accessibility of blood-based biomarkers (BBMs) like p-tau217 and Aβ42/40 offers a scalable way to investigate these relationships.
OBJECTIVES: To examine the relationship between ADI and levels of key BBMs (p-tau217/Aβ42, p-tau217, and Aβ42/40). We also aimed to assess whether the performance of these BBMs in predicting amyloid PET positivity is consistent across different levels of neighborhood disadvantage.
DESIGN: A cross-sectional analysis using data from an observational cohort study of the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
SETTING: Multicenter observational cohort conducted at 55 sites across the United States.
PARTICIPANTS: The study included 755 ADNI participants with ADI and amyloid PET data. A sub-cohort of 438 participants also had BBM data available.
MEASUREMENTS: National ADI scores were used to stratify participants into least, intermediately, and most disadvantaged groups. Amyloid PET positivity was determined using Centiloid values. Plasma levels of p-tau217, Aβ42, and Aβ40 were measured using Fujirebio assays.
RESULTS: ADI groups differed by sex, ethnoracial background, and MMSE scores. The intermediately disadvantaged group had 1.55 times higher odds of being amyloid PET positive compared to the least disadvantaged group. While this group also showed higher levels of plasma p-tau217/Aβ42 and p-tau217, these differences were no longer significant after accounting for the higher prevalence of amyloid positivity. Critically, the predictive accuracy of all three BBMs for amyloid PET status did not differ across the ADI groups. The p-tau217/Aβ42 ratio performed best, yielding the fewest indeterminate cases in a two-cut-point classification model.
CONCLUSIONS: The diagnostic performance of plasma AD biomarkers is robust and is not compromised by neighborhood-level disadvantage. These findings support the generalizability and equitable clinical utility of biomarkers like p-tau217/Aβ42 for AD diagnosis across diverse socioeconomic settings.
CITATION:
Alison Myoraku ; Isabella Hausle ; Marta Mila-Aloma ; Pamela Thropp ; Laura A. Wang ; P. Murali Doraiswamy ; Duygu Tosun ; Alzheimer’s Disease Neuroimaging Initiative (2025): Association of neighborhood disadvantage with Alzheimer's disease pathology and the stability of blood-based biomarker performance. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100445
ASSOCIATION OF LIFE’S SIMPLE 7 WITH COGNITIVE FUNCTION IN A MULTI-ETHNIC COHORT
Xiangyuan Huang, Muhammad Haiman Bin Samad, Gerald Choon Huat Koh, Andre Matthias Müller, Falk Müller-Riemenschneider, Xueling Sim, Saima Hilal
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND AND OBJECTIVES: Multiple lifestyle and health factors could contribute to cognitive health, while not many studies examined the factors in a combined way, especially in Asian population. This study aims to examine the association of Life’s Simple 7 (LS7) with cognitive function and its change in a multi-ethnic Asian population.
METHODS: Longitudinal data were drawn from the Singapore Multi-Ethnic Cohort, involving 2601 participants (45–86 years). LS7 at baseline was calculated by summing seven metrics, and a higher LS7 (range: 0–7) score indicates a healthier lifestyle. Cognitive function was measured at two revisits with Mini-Mental State Examination (MMSE). Association of baseline LS7 with MMSE percentiles (10th, 30th and 50th) and its change over time were examined using linear quantile mixed model. Interactions between LS7 and age group, sex, ethnicity, education level and marital status were also explored.
RESULTS: Higher LS7 was significantly associated with higher MMSE scores at 10th (β = 0.11, 95% CI 0.01, 0.20), 30th (β = 0.12, 95% CI 0.05, 0.19), and 50th (β = 0.07, 95% CI 0.03, 0.11) percentiles. These associations were particularly pronounced among currently unmarried individuals, participants aged 60 and above, those with education above primary school and Chinese ethnicity. No significant association was found between LS7 and MMSE change over time.
DISCUSSION: Higher LS7 was significantly associated with better cognition particularly among older, unmarried individuals and participants with higher education or of Chinese ethnicity. These findings highlight the value of composite lifestyle scores for cognitive impairment risk modification in Asian populations.
CITATION:
Xiangyuan Huang ; Muhammad Haiman Bin Samad ; Gerald Choon Huat Koh ; Andre Matthias Müller ; Falk Müller-Riemenschneider ; Xueling Sim ; Saima Hilal (2025): Association of life’s simple 7 with cognitive function in a multi-ethnic cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100453
A REVIEW OF EVIDENCE SUPPORTING AMYLOID BETA REDUCTION AS A SURROGATE ENDPOINT IN ALZHEIMER’S DISEASE
Tianle Chen, R. Matthew Hutchison, Carrie Rubel, Jennifer Murphy, Jing Xie, John O’Gorman, Gersham Dent, Geert Molenberghs, Maria Pia Sormani, Suzanne Hendrix, Oskar Hansson, Paul Aisen, Samantha Budd Haeberlein, Ying Tian
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryAlzheimer’s disease (AD) is a heterogeneous neurodegenerative disease driven by pathological depositions of proteins that accumulate over decades. Compelling genetic and neurobiological evidence suggests that amyloid accumulation in the brain initiates and drives early-stage AD. Measurement of fibrillar amyloid has been pivotal to the development and approval of disease-slowing treatments. Various biomarkers of AD pathophysiology provide evidence of target engagement and downstream effects on disease progression, and their use as surrogate endpoints may help identify and expeditiously bring new treatments to patients. In clinical trials, a surrogate endpoint serves as a substitute for a direct measurement of a patient’s clinical status, and its use can provide ethical, logistical, and economic advantages. Establishing biomarkers as surrogate endpoints involves evaluating scientific evidence through diverse statistical approaches to demonstrate their predictivity of clinical benefit. This article evaluated evidence supporting amyloid β plaque reduction as a surrogate endpoint in symptomatic AD by exploring regulatory considerations and guidelines for surrogate endpoints, examining the amyloid hypothesis and the current therapeutic landscape in AD, and presenting supporting evidence of surrogate endpoints from a recent clinical development program of AD.
CITATION:
Tianle Chen ; R. Matthew Hutchison ; Carrie Rubel ; Jennifer Murphy ; Jing Xie ; John O’Gorman ; Gersham Dent ; Geert Molenberghs ; Maria Pia Sormani ; Suzanne Hendrix ; Oskar Hansson ; Paul Aisen ; Samantha Budd Haeberlein ; Ying Tian (2025): A review of evidence supporting amyloid beta reduction as a surrogate endpoint in Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100458
DONANEMAB IN EARLY SYMPTOMATIC ALZHEIMER’S DISEASE: RESULTS FROM THE TRAILBLAZER-ALZ 2 LONG-TERM EXTENSION
Jennifer A. Zimmer, John R. Sims, Cynthia D. Evans, Emel Serap Monkul Nery, Hong Wang, Alette M. Wessels, Giulia Tronchin, Shoichiro Sato, Lars Lau Raket, Lars Lau Raket, Christophe Sapin, Marie-Ange Paget, Ivelina Gueorguieva, Paul Ardayfio, Rashna Khanna, Dawn A. Brooks, Brandy R. Matthews, Mark A. Mintun, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: Donanemab significantly slowed clinical progression in participants with early symptomatic Alzheimer’s disease (AD) during the 76-week placebo-controlled period of TRAILBLAZER-ALZ 2.
METHODS: Participants who completed the placebo-controlled period were eligible for the 78-week, double-blind, long-term extension (LTE). Early-start participants were randomized to donanemab in the placebo-controlled period. Delayed-start participants (randomized to placebo) started donanemab in the LTE. Participants who met amyloid treatment course completion criteria were switched to placebo. An external control cohort comprised participants from the AD Neuroimaging Initiative (ADNI).
RESULTS: At 3 years, donanemab slowed disease progression on the Clinical Dementia Rating Scale (CDR)-Sum of Boxes (CDR-SB) in early-start participants versus a weighted ADNI control (-1.2 points; 95 % confidence interval [CI], -1.7, -0.7). Seventy-six weeks after initiating donanemab, delayed-start participants also demonstrated slower CDR-SB progression versus a weighted ADNI control (-0.8 points; 95 % CI, -1.3, -0.3). Participants who completed treatment by 52 weeks demonstrated similar slowing of CDR-SB progression at 3 years. Compared with delayed-start participants, early-start participants demonstrated a significantly lower risk of disease progression on the CDR-Global over 3 years (hazard ratio=0.73; p < 0.001). In both groups, >75 % of participants assessed by positron emission tomography 76 weeks after starting donanemab achieved amyloid clearance (<24.1 Centiloids). The addition of LTE data to prior modeling predicted a median reaccumulation rate of 2.4 Centiloids/year. No new safety signals were observed compared to the established donanemab safety profile.
CONCLUSIONS: Over 3 years, donanemab-treated participants with early symptomatic AD demonstrated increasing clinical benefits and a consistent safety profile, with limited-duration dosing.
CITATION:
Jennifer A. Zimmer ; John R. Sims ; Cynthia D. Evans ; Emel Serap Monkul Nery ; Hong Wang ; Alette M. Wessels ; Giulia Tronchin ; Shoichiro Sato ; Lars Lau Raket ; Scott W. Andersen ; Christophe Sapin ; Marie-Ange Paget ; Ivelina Gueorguieva ; Paul Ardayfio ; Rashna Khanna ; Dawn A. Brooks ; Brandy R. Matthews ; Mark A. Mintun ; Alzheimer’s Disease Neuroimaging Initiative (2025): Donanemab in early symptomatic Alzheimer’s disease: results from the TRAILBLAZER-ALZ 2 long-term extension. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100446
TAU IN ALZHEIMER\'S DISEASE: SHAPING THE FUTURE PATIENT JOURNEY
Catherine J. Mummery, Christopher Chen Li-Hsian, Cristian A. Lasagna-Reeves, Rik Ossenkoppele, Christopher C. Rowe, Douglas W. Scharre, Huali Wang, Simon Kyaga, Jeffrey L. Cummings
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryAlzheimer’s disease is a complex and multifactorial disease characterized by two key pathological hallmarks: amyloid-beta plaques and tau neurofibrillary tangles. Recent progress has led to the development and approval of disease-targeted therapies for Alzheimer’s disease in the form of anti-amyloid-beta monoclonal antibodies. However, findings suggest that amelioration of multiple pathological drivers may be required to maximize clinical effect. An increasing body of evidence suggests that tau is a critical player in Alzheimer’s disease pathophysiology, contributing significantly to neurodegeneration and cognitive decline. There are now several tau-targeting drugs in clinical development. In this review, we build on research and advancements in the field of tau to envision how an increasing focus on tau could shape the future Alzheimer’s disease patient journey. We highlight the potential of tau as both a promising therapeutic target and a valuable biomarker, with the potential to inform treatment decisions and provide insight into disease trajectories. We also consider what a greater focus on tau may bring to an already evolving patient care pathway characterized by an increased influx of patients presenting earlier in the disease continuum, changes in workflow and infrastructural requirements, and increased complexity in treatment decision-making, treatment administration, treatment monitoring, and patient tracking. This review underscores the critical changes that may be required and knowledge gaps to be elucidated to ensure healthcare system preparedness for additional classes of disease-targeted therapy to move toward a next-generation, individualized treatment approach to Alzheimer’s disease diagnosis and care.
CITATION:
Catherine J. Mummery ; Christopher Chen Li-Hsian ; Cristian A. Lasagna-Reeves ; Rik Ossenkoppele ; Christopher C. Rowe ; Douglas W. Scharre ; Huali Wang ; Simon Kyaga ; Jeffrey L. Cummings (2025): Tau in Alzheimer's disease: Shaping the future patient journey. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100447
SYSTEMATIC POST-TRANSLATIONAL MODIFICATION GENOME WIDE IDENTIFIES THERAPEUTIC TARGETS FOR ALZHEIMER’S DISEASE: EVIDENCE FROM MULTI-COHORT ANALYSIS
Xiaoming Wang, Yuancheng Liu, Juncai Fu, Yizhao Li, Mengying Zhao, Qing Tian
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: The rapid increase in the incidence of Alzheimer’s disease (AD) has raised concerns, given its profound effects on both society and the economy. Despite extensive research efforts in this area, there are no existing treatments that have the ability to change the progression of the disease.
METHODS: To identify the distinct subtypes of AD, consensus clustering was employed. Following this, module genes were identified through the implementation of WGCNA. In addition, the investigation included the identification of hub genes through the application of machine learning. Ultimately, a thorough analysis was performed utilizing a methodical strategy to perform post-translational modification (PTM) genome wide.
RESULTS: GO and KEGG analyses were conducted by examining of 21 different types of PTMs, revealing that the majority of these genes play key roles in the PTM pathways, as well as AD-related pathways. Correlation analysis revealed that these PTM were significantly correlated with gamma secretase activity, beta secretase activity, amyloid-beta 42, clinical dementia rating, Braak stage, plaque, and neurofibrillary tangle. Then, two distinct subtypes of PTM were identified, each characterized by unique clinical characteristic. By utilizing machine learning, we developed an PTM.score, and has shown impressive predictive capabilities for AD when tested against various datasets (brain AUC: 0.859, blood AUC: 0.898), indicating its potential utility in clinical settings for risk stratification and therapeutic decision-making. Moreover, our investigation led to the identification of two genes (TRIM47 and LNX1) that may represent potential drug targets for AD (brain tissues or blood samples). Research further indicated a potential correlation between TRIM47 and concentrations of CSF Aβ (OR 1.068 (1.029–1.108)), CSF p-tau (OR 1.315 (1.136–1.524)), and total hippocampal (OR 1.176 (1.058–1.307)).
CONCLUSIONS: The findings from this study not only enhance our comprehension of the underlying mechanisms of AD but also serve to inform and direct future initiatives in drug discovery. By focusing on TRIM47, the work paves the way for identifying innovative therapeutic strategies.
CITATION:
Xiaoming Wang ; Yuancheng Liu ; Juncai Fu ; Yizhao Li ; Mengying Zhao ; Qing Tian (2025): Systematic post-translational modification genome wide identifies therapeutic targets for Alzheimer’s disease: evidence from multi-cohort analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100422>
ASSOCIATIONS OF PLASMA BIOMARKERS WITH LONGITUDINAL CO-PATHOLOGIES IN ALZHEIMER’S DISEASE AND CEREBRAL SMALL VESSEL DISEASE COMORBIDITY
Jing Yang, Xinyuan Zhao, Yidan Liu, Yangwei Cai, Yuhua Fan, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: Plasma glial fibrillary acidic protein (GFAP), neurofilament light (NfL), phosphorylated tau217 (p-tau217), and the β-amyloid (Aβ) 42/40 ratio are emerging indicators of neuroinflammation, neurodegeneration, and AD-specific pathology, while their specific roles within Alzheimer’s disease (AD) and cerebral small vessel disease (CSVD) comorbidity are not fully understood.
METHODS: Participants with normal cognition or mild cognitive impairment were drawn from the Alzheimer’s Disease Neuroimaging Initiative database. Multivariable linear regression and linear mixed-effects models were employed to examine associations of baseline plasma biomarkers with neuropathological features and cognition. Furthermore, Cox proportional hazards models assessed the associations of plasma biomarkers with the risk of comorbid AD and CSVD.
RESULTS: In total populations, elevated GFAP and p-tau217 were significantly associated with greater white matter hyperintensity (WMH) burden, hippocampal atrophy, cerebral Aβ burden, and cognitive decline at baseline and with progression over time (|β| = 0.007 to 1.670, p = 0.047 to <0.0001). Within disease-specific subgroups, GFAP, p-tau217, and Aβ42/40 ratio demonstrated associations with hippocampal atrophy or WMH progression in CSVD (|β| = 0.011 to 0.220, p = 0.046 to 0.010), whereas GFAP, NfL, p-tau217, and Aβ42/40 ratio were linked to hippocampal atrophy and/or WMH progression in typical AD (|β| = 0.013 to 0.191, p = 0.044 to 0.0002). For Cox proportional hazards models, p-tau217 demonstrated greater precision in predicting progression to the CSVD phenotype within the AD subgroup (Hazard ratios = 1.267 to 3.811, p = 0.046 to 0.034).
CONCLUSION: These findings underscore the potential role of plasma biomarkers in elucidating the synergistic mechanisms underlying AD and CSVD comorbidity.
CITATION:
Jing Yang ; Xinyuan Zhao ; Yidan Liu ; Yangwei Cai ; Yuhua Fan ; Alzheimer’s Disease Neuroimaging Initiative (2025): Associations of plasma biomarkers with longitudinal co-pathologies in Alzheimer’s disease and cerebral small vessel disease comorbidity. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100449
TRAJECTORY OF COGNITIVE DECLINE BEFORE AND AFTER INCIDENT HEART FAILURE AMONG OLDER ADULTS: A 20-YEAR, POPULATION-BASED, PROSPECTIVE COHORT STUDY
Haibin Li, Frank Qian, Wuxiang Xie, Man Wang, Jianian Hua, Jiao Wang, Xinye Zou, Zhiyuan Wu, Xia Li, Deqiang Zheng, Xiuhua Guo, Hongjia Zhang
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: The magnitude of cognitive change before and after incident heart failure (HF) is unclear. We investigated whether incident HF is associated with changes in cognitive function at the time of diagnosis and accelerated trajectory in cognitive decline in the subsequent years.
METHODS: We used data from the Health and Retirement Study, a nationally representative survey of US adults aged 50 years or older. Participants underwent a cognitive assessment at baseline (wave 5, 2000), and at least 1 other time point (from wave 6 [2002] to wave 15 [2020]). The outcomes were change in global cognition, memory, and executive function. Outcomes were standardized into Z-scores, with higher scores indicating better cognitive performance. Linear mixed-effects models estimated changes in cognition at the time of HF (change in the intercept) and the rate of cognitive change over the years after HF (change in the slope), after adjusting for pre-HF cognitive trajectories and potential confounders.
RESULTS: We included 12 850 adults (mean [SD] age, 66.1 [9.4] years; 61.8 % women). Over a median follow-up of 16 years (interquartile range: 8 to 20 years), 1457 participants had incident HF. The annual rate of cognitive decline before HF diagnosis among individuals with incident HF was similar to that of participants who remained HF-free throughout follow-up. However, incident HF was associated with subsequent decreases in global cognition (−0.073 SD [95 % CI −0.109 to −0.038]), memory (−0.070 SD [95 % CI −0.108 to −0.032]), and executive function (−0.054 SD [95 % CI −0.092 to −0.016]) around the time of the HF diagnosis. Moreover, individuals with incident HF vs those without HF demonstrated faster and long-term declines in global cognition (−0.011 SD/year [95 % CI −0.018 to −0.004]) and executive function (−0.008 SD/year [95 % CI −0.015 to −0.001]), but not in memory (−0.006 SD/year [95 % CI −0.013 to 0.001]) over the years after HF compared with pre-HF slopes.
CONCLUSIONS: Incident HF was associated with subsequent decreases in cognitive function at the time of diagnosis and accelerated cognitive decline over the following years.
CITATION:
Haibin Li ; Frank Qian ; Wuxiang Xie ; Man Wang ; Jianian Hua ; Jiao Wang ; Xinye Zou ; Zhiyuan Wu ; Xia Li ; Deqiang Zheng ; Xiuhua Guo ; Hongjia Zhang (2025): Trajectory of cognitive decline before and after incident heart failure among older adults: A 20-Year, population-based, prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100450
IRON DYSREGULATION IN CEREBRAL SMALL VESSEL DISEASE: A QUANTITATIVE SUSCEPTIBILITY MAPPING STUDY REVEALING SPATIAL PATTERNS AND COGNITIVE PREDICTIVE VALUE
Pengcheng Liang, Meng Li, Qihao Zhang, Nan Zhang, Yena Che, Yian Gao, Chaofan Sui, Xinyue Zhang, Na Wang, Yuanyuan Wang, Yiwen Chen, Zhenyu Cheng, Changhu Liang, Lingfei Guo, Jing Li
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: White matter hyperintensities (WMHs) represent a cardinal feature of cerebral small vessel disease (CSVD), yet iron dysregulation alterations within these lesions and their relationship to cognitive decline remains poorly understood.
OBJECTIVES: To characterize iron dysregulation in WMH using quantitative susceptibility mapping (QSM) and examine their relationship with CSVD severity and cognitive function.
DESIGN: Cross-sectional study with longitudinal follow-up component.
SETTING: Single-center study at Shandong Provincial Hospital Affiliated with Shandong First Medical University, China.
PARTICIPANTS: 299 participants recruited from January 2021 to September 2023, with 71 participants completing longitudinal follow-up (mean interval 20.6 months). Participants were categorized into early CSVD (0 points, n = 171), mild CSVD (1 point, n = 70), and severe CSVD (≥2 points, n = 58) groups based on total burden scoring.
INTERVENTION: None (observational study).
MEASUREMENTS: 3.0T MRI with quantitative susceptibility mapping and diffusion tensor imaging. Spatial analysis examined susceptibility values in WMH cores and perilesional zones (0–2 mm, 2–4 mm, 4–6 mm). Cognitive assessments included Montreal Cognitive Assessment (MoCA), Symbol Digit Modalities Test (SDMT), and other neuropsychological tests.
RESULTS: WMH susceptibility values were significantly lower than normal-appearing white matter (-14.55 vs -7.77 ppb, P < 0.001) with progressive increases correlating with CSVD severity (P < 0.001). Cross-sectionally, higher WMH susceptibility values correlated with lower MoCA scores (r = -0.155, P = 0.045). Longitudinally, WMH susceptibility values predicted decline in information processing speed (SDMT: β = -0.247, P = 0.042). Spatial analysis revealed distinct patterns with perilesional regions showing intermediate susceptibility values.
CONCLUSIONS: Iron dysregulation alterations within WMH provide independent information about cognitive risk in CSVD. QSM emerges as a promising biomarker for monitoring cognitive trajectory and may facilitate early identification of patients at risk for cognitive decline.
CITATION:
Pengcheng Liang ; Meng Li ; Qihao Zhang ; Nan Zhang ; Yena Che ; Yian Gao ; Chaofan Sui ; Xinyue Zhang ; Na Wang ; Yuanyuan Wang ; Yiwen Chen ; Zhenyu Cheng ; Changhu Liang ; Lingfei Guo ; Jing Li (2025): Iron dysregulation in cerebral small vessel disease: A quantitative susceptibility mapping study revealing spatial patterns and cognitive predictive value. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100451
MULTI-OMICS INTEGRATION REVEALS SHARED GENETIC ARCHITECTURE BETWEEN METABOLIC MARKERS AND GRAY MATTER ATROPHY IN ALZHEIMER’S DISEASE
Piaoran Wang, Xiangzheng Wu, Fengyu Sun, Hongchuan Zhang, Yurong Jiang, Qiuhui Wang, Hao Ding, Yujing Zhou, Feng Liu, Huaigui Liu
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by widespread gray matter volume (GMV) reductions. Emerging evidence links glucose and lipid metabolic dysregulation to AD pathophysiology. However, the extent to which AD-related GMV alterations and metabolic traits share a common genetic basis remains poorly understood.
OBJECTIVES: To explore the shared genetic architecture between GMV alterations in AD and metabolites related to glucose and lipid metabolism, aiming to provide biological insights into the prevention and treatment of AD.
DESING: This is a multimodal, cross-disciplinary study combining neuroimaging meta-analysis, transcriptome-neuroimaging association analysis, conjunctional false discovery rate (conjFDR) analysis, and functional enrichment analysis to identify the shared genetic architecture between AD-related brain structural alterations and metabolic traits.
SETTING: Public databases and European populations.
PARTICIPANTS: The meta-analysis included 49 studies (1945 CE patients and 2598 controls). The largest genome-wide association study (GWAS) summary statistics were used for AD (Ncase = 39,918; Ncontrol =358,140), two glycemic traits—glucose (GLU, N = 459,772) and glycated hemoglobin (HbA1c, N = 146,864), and three lipid traits (N = 1320,016)—high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG).
MEASUREMENTS: We conducted a voxel-based morphometric meta-analysis of GMV in AD by systematically reviewing 49 neuroimaging studies, identified through a literature search in PubMed and Web of Science using a predefined search strategy. Building upon these neuroanatomical findings, we performed a transcriptome-neuroimaging association analysis using data from the Allen Human Brain Atlas to identify genes spatially correlated with GMV alterations. To further explore the shared genetic architecture, we integrated GWAS summary statistics for AD and five metabolic markers using conjFDR analysis. Finally, functional enrichment analyses were performed to elucidate the biological relevance of the identified genes through this integrative framework.
RESULTS: Consistent GMV reductions in AD were observed in the bilateral middle temporal gyrus, right superior temporal gyrus, and other key subcortical regions. The conjFDR analysis identified 20, 17, 78, 87, and 82 genes shared between AD-related GMV reductions and GLU, HbA1c, HDL-C, LDL-C, and TG, respectively. Notably, 6 genes were shared across all five metabolic markers. Enrichment analysis implicated these genes in biological processes related to Aβ aggregation and phosphatidylinositol metabolism.
CONCLUSIONS: This study reveals a convergent genetic architecture underlying AD-related GMV atrophy and metabolic dysfunction. These findings may offer novel insights into the molecular interplay between systemic metabolism and neurodegeneration in AD and highlight potential targets for therapeutic strategies.
CITATION:
Piaoran Wang ; Xiangzheng Wu ; Fengyu Sun ; Hongchuan Zhang ; Yurong Jiang ; Qiuhui Wang ; Hao Ding ; Yujing Zhou ; Feng Liu ; Huaigui Liu (2025): Multi-omics integration reveals shared genetic architecture between metabolic markers and gray matter atrophy in Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100452
HIPPOCAMPAL MICROSTRUCTURE AS A MEASURE OF COGNITIVE RESILIENCE TO TAU PET BURDEN IN OLDER ADULTS
Daniel D. Callow, Nisha Rani, Kylie H. Alm, Corinne Pettigrew, Michael Miller, Marilyn Albert, Arnold Bakker, Anja Soldan, the BIOCARD Research Team
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: Cognitive resilience, the ability to maintain better than expected cognitive function despite neuropathological burden, is a key contributor to clinical outcomes in Alzheimer’s disease (AD), though the underlying neurobiological mechanisms remain poorly understood.
OBJECTIVES: To determine whether hippocampal volume and microstructure moderate the relationship between early tau pathology and cognitive performance, thereby serving as potential markers of cognitive resilience.
DESIGN: Cross-sectional observational study.
SETTING: Participant data was obtained from the longitudinal BIOCARD Study, a volunteer-based research cohort.
PARTICIPANTS: The sample included 190 dementia-free adults (mean age = 68 years), comprising 176 cognitively unimpaired individuals and 14 with mild cognitive impairment (MCI).
MEASUREMENTS: Hippocampal volume and microstructure (mean diffusivity (MD)) were measured using structural magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI), respectively. Tau pathology was measured using FMK-6240 tau PET imaging across Braak stages I–III. Cognitive performance was indexed using global and domain-specific composite scores. Regression models tested the interactions between hippocampal volume or MD and tau burden, adjusting for demographics, APOE genotype, amyloid status, and diagnostic status.
RESULTS: Lower hippocampal MD (indicative of better microstructural integrity) attenuated the negative association between tau burden in Braak stages II–III and both global cognition and episodic memory (ps < 0.010). Logistic regression models indicated that lower hippocampal MD was associated with a weaker relationship between tau burden in Braak stages II–III and the likelihood of MCI diagnosis (ps < 0.050). In contrast, hippocampal volume did not moderate the relationship between tau and any cognitive outcome (ps > 0.250).
CONCLUSIONS: Hippocampal MD may serve as a promising imaging marker of cognitive resilience to early tau pathology, with potential utility for risk stratification and as a target for preventive interventions in AD.
CITATION:
Daniel D. Callow ; Nisha Rani ; Kylie H. Alm ; Corinne Pettigrew ; Michael Miller ; Marilyn Albert ; Arnold Bakker ; Anja Soldan ; the BIOCARD Research Team (2025): Hippocampal microstructure as a measure of cognitive resilience to tau PET burden in older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100454
PLASMA AΒ42/40 PREDICTS PROGRESSION FROM AΒ-AMYLOID NEGATIVE TO POSITIVE PET SCANS
Azadeh Feizpour, Vincent Doré, Pierrick Bourgeat, James D. Doecke, Rodrigo Canovas, Simon M. Laws, Tenielle Porter, Kun Huang, Christopher Fowler, Ralph N. Martins, Paul Maruff, Hamid R. Sohrabi, Michael W. Weiner, John C. Morris, Tammie L.S. Benzinger, Suzanne E. Schindler, Randall J. Bateman, Yan Li, Ovod Vitaliy, Larry Ward, Jurgen Mejan-Fripp, Colin L. Masters, Victor L. Villemagne, Christopher C. Rowe, ADOPIC Consortium (AIBL, ADNI, OASIS)
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: The agreement between plasma Aβ42/40 and Aβ positron emission tomography (PET) is approximately 75 %, with ∼85 % of discrepancies due to positive plasma but negative PET results. It is unclear whether this reflects Aβ changes in plasma before PET-detectable.
OBJECTIVES: To assess the influence of Aβ42/40 positivity on risk of progression to Aβ PET positivity, and feasibility of using plasma Aβ42/40 tests to enrich a primary prevention trial.
DESIGN: A prospective longitudinal cohort study.
SETTING: Participants of Australian Imaging, Biomarkers and Lifestyle study (AIBL), Alzheimer’s Disease Neuroimaging Initiative (ADNI), and Open Access Series of Imaging Studies 3 (OASIS3).
PARTICIPANTS: 507 cognitively unimpaired adults at baseline, with a baseline Aβ PET < 20 Centiloid (CL) and available longitudinal Aβ PET data.
MEASUREMENTS: Baseline Aβ PET and plasma Aβ42/40 measurement by mass-spectrometry, followed by 1–6 additional Aβ PET scans every 1.5–3 years. Those < 5 CL were classified as PET- and 5–20 CL as PETLow. Plasma -/+ was defined using the Aβ42/40 Youden’s Index threshold (0.119), corresponding to Aβ PET status.
RESULTS: At baseline, 283 were Plasma-/PET-, 97 Plasma+/PET-, 76 Plasma-/PETLow, and 51 Plasma+/PETLow. Among Plasma+/PET- individuals, 19 % progressed to PET+ (>20 CL), indicating a higher risk of progression, compared to Plasma-/PET- (HR: 3.90 [90 % CI: 2.00–7.61], p < 0.001). This elevated risk remained significant after matching the groups’ baseline CL (3.43 [1.43–8.26], p = 0.010), or adjustment for age, sex, APOE ε4 and baseline CL (2.48 [1.22 - 5.07], p = 0.013). Plasma+/PET- individuals accumulated Aβ ∼8 times faster (1.14 CL/year) than Plasma-/PET- (0.15 CL/year, p < 0.001). Plasma+/PET- progressors became PET+ two years earlier than Plasma-/PET- progressors. Among the Plasma+/PETLow individuals, 67 % progressed to PET+. Their progression was faster and earlier than in the Plasma-/PETLow group (HR: 20.82 [11.28 - 38.42], p < 0.001 vs. 6.67 [3.51 - 12.65], p < 0.001; reference: Plasma-/PET-), largely driven by higher baseline CL in the Plasma+ group. In a primary prevention paradigm targeting high-risk PETLow individuals, pre-screening with Aβ42/40 blood test reduced the number of PET scans by 49 %, compared to a PET-only strategy.
Conclusions
Cognitively unimpaired individuals with abnormal Aβ42/40 are at increased risk for future Aβ PET positivity. In the 5–20 CL subgroup, baseline CL is the main driver of this risk. Combining blood-based pre-screening with PET imaging may help efficiently enrich primary prevention trials.
CITATION:
Azadeh Feizpour ; Vincent Doré ; Pierrick Bourgeat ; James D. Doecke ; Rodrigo Canovas ; Simon M. Laws ; Tenielle Porter ; Kun Huang ; Christopher Fowler ; Ralph N. Martins ; Paul Maruff ; Hamid R. Sohrabi ; Michael W. Weiner ; John C. Morris ; Tammie L.S. Benzinger ; Suzanne E. Schindler ; Randall J. Bateman ; Yan Li ; Ovod Vitaliy ; Larry Ward ; Jurgen Mejan-Fripp ; Colin L. Masters ; Victor L. Villemagne ; Christopher C. Rowe ; ADOPIC Consortium (AIBL, ADNI, OASIS) (2025): Plasma Aβ42/40 predicts progression from Aβ-amyloid negative to positive PET scans. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100455
SYNAPTIC TOXICITY OF OGA INHIBITORS AND THE FAILURE OF CEPEROGNASTAT
Jonathan Meade, Haylee Mesa, Shahriar Alamgir, Isabell Bieniecka, Lei Liu, Qi Zhang
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryO-GlcNAcase inhibitors (OGAi) have emerged as a promising therapeutic strategy in Alzheimer’s disease (AD) by enhancing O-GlcNAcylation, which competes with tau phosphorylation and reduces tau aggregation. However, the Phase II clinical trial failure of ceperognastat, marked by accelerated cognitive decline in the treatment group, has raised significant safety concerns. Here, we examined the acute synaptic effects of three structurally distinct OGAi compounds—ceperognastat, ASN90, and MK8719—in mouse hippocampal slices. Electrophysiological recordings revealed suppression of both short- and long-term synaptic plasticity, including paired-pulse facilitation/depression and long-term potentiation. Immunohistochemical analysis confirmed disrupted synaptic protein levels (increased PSD-95, reduced Synaptophysin 1) and a biphasic shift in tau phosphorylation. These convergent findings suggest a class-wide synaptotoxic mechanism and call for a great caution in the development of disease-modifying therapies in AD. We argue that preclinical drug screening for synaptic functionality is essential in CNS-targeted therapeutic pipelines.
CITATION:
Jonathan Meade ; Haylee Mesa ; Shahriar Alamgir ; Isabell Bieniecka ; Lei Liu ; Qi Zhang (2025): Synaptic toxicity of OGA inhibitors and the failure of ceperognastat. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100456
SOLUBLE AND PLAQUE AMYLOID ASSOCIATIONS WITH PERIPHERAL GLUCOSE DYSREGULATION MODULATED BY TAU PATHOLOGY IN ALZHEIMER’S DISEASE
Dong Woo Kang, Suhyung Kim, Sunghwan Kim, Yoo Hyun Um, Sheng-Min Wang, Seunggyun Ha, Sonya Youngju Park, Seung-Hwan Lee, Yeong Sim Choe, Donghyeon Kim, Chang Uk Lee, Hyun Kook Lim
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: Glucose metabolic dysfunction in Alzheimer’s disease (AD) has been reported to be associated with soluble amyloid-β oligomers (OAβ) and plaque amyloid. However, the potential modulatory role of tau pathology in these associations remains to be fully elucidated.
OBJECTIVES: To investigate whether tau pathology modifies the relationship between plasma OAβ burden, plaque amyloid, and systemic glucose metabolism in individuals across the AD spectrum.
DESIGN: Cross-sectional observational study.
SETTING: Memory clinic-based cohort from a single tertiary academic medical center in Republic of Korea.
PARTICIPANTS: A total of 113 older adults, including cognitively normal individuals, patients with mild cognitive impairment, and Aβ-PET–positive dementia patients.
MEASUREMENTS: Plasma oligomeric Aβ (OAβ) levels were measured in blood samples using the Multimer Detection System, which quantifies oligomeric forms of Aβ in plasma. Aβ plaque deposition was assessed using [18F]-flutemetamol PET, and tau pathology was assessed using [18F]-flortaucipir PET, from which Braak staging was determined. Glucose metabolism was evaluated using fasting plasma glucose and hemoglobin A1c (HbA1c). Generalized linear models were used to examine the associations and potential interactions between plasma OAβ burden and plaque Aβ with tau pathology, adjusting for clinical covariates.
RESULTS: A significant interaction was identified between plasma OAβ levels and Braak stage III/IV, but not Braak I or V/VI, when referenced to Braak 0. Only at Braak 0, higher plasma OAβ levels were associated with higher HbA1c compared with Braak stage III/IV (β = −4.191, 95 % CI −7.714 to −0.669, p = 0.020). No significant interactions were observed for fasting glucose or for Aβ-PET SUVR. Sensitivity analyses adjusting for diabetes diagnosis and excluding dementia participants confirmed the robustness of these findings.
CONCLUSION: Soluble Aβ oligomers, rather than plaque amyloid, are selectively associated with systemic glucose dysregulation in the absence of overt tau pathology. Tau staging may be crucial for identifying AD subgroups vulnerable to metabolic dysfunction potentially associated with early Aβ toxicity.
CITATION:
Dong Woo Kang ; Suhyung Kim ; Sunghwan Kim ; Yoo Hyun Um ; Sheng-Min Wang ; Seunggyun Ha ; Sonya Youngju Park ; Seung-Hwan Lee ; Yeong Sim Choe ; Donghyeon Kim ; Chang Uk Lee ; Hyun Kook Lim (2025): Soluble and plaque amyloid associations with peripheral glucose dysregulation modulated by tau pathology in Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100459
COST-EFFECTIVENESS OF MULTIMODAL INTERVENTION FOR THE PREVENTION OF DEMENTIA IN JAPAN
Naoki Takashi, Shosuke Ohtera, Yujiro Kuroda, Hidenori Arai, Takashi Sakurai, J-MINT investigators
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: This analysis evaluated the potential cost-effectiveness of the Japan-Multimodal Intervention Trial for the prevention of dementia (J-MINT), targeting older adults with mild cognitive impairment (MCI) from a societal perspective.
METHODS: Using a time-dependent cohort state-transition model, we estimated the long-term economic impact of J-MINT. Costs included medical, long-term, and informal care. Incremental cost-effectiveness ratios (ICERs) were calculated based on simulated costs and quality-adjusted life years (QALYs).
RESULTS: The base-case analysis indicated that the J-MINT was dominant, demonstrating cost saving and more effective compared to usual care. Over 35 years, J-MINT was projected to achieve cost savings of JPY 452,826 per person and a gain of 0.08 QALYs. Deterministic and probabilistic sensitivity analyses confirmed the robustness of these findings. Scenario analysis suggested that targeting APOE ε4 carriers or individuals with high adherence to exercise yielded even greater benefits.
CONCLUSION: J-MINT demonstrates cost-effectiveness by reducing overall care costs while improving QALYs in individuals with MCI.
CITATION:
Naoki Takashi ; Shosuke Ohtera ; Yujiro Kuroda ; Hidenori Arai ; Takashi Sakurai ; J-MINT investigators (2025): Cost-effectiveness of multimodal intervention for the prevention of dementia in Japan. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100460
INDIVIDUALIZED PREDICTION OF TRANSITION FROM SUBJECTIVE COGNITIVE DECLINE TO MILD COGNITIVE IMPAIRMENT BASED ON MULTIMODAL MRI: A 10-YEAR FOLLOW-UP STUDY
Xingyan Le, Junbang Feng, Xiaoli Yu, Yuyin Wang, Qingbiao Zhang, Yuwei Xia, Feng Shi, Chuanming Li
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: Predicting the transition from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) is critical for dementia prevention.
OBJECTIVE: Comprehensive assessment of MRI-based macro-/micro-structural and functional brain changes in SCD to develop an individualized model predicting transition to MCI.
DESIGN, SETTING, AND PARTICIPANTS: Patients with SCD were screened from the ADNI, NACC, and OASIS-3 databases. 89 patients met the inclusion criteria and underwent structural magnetic resonance imaging (sMRI) and resting-state functional MRI (rs-fMRI). Over a 10-year follow-up, 49 patients progressed to MCI, while 40 remained stable.
MEASUREMENTS: The VB-net automated brain segmentation, extracting hippocampal radiomics and whole brain subregion volume features. Brain functional features were extracted based on rs-fMRI. Cox regression was used to develop predictive models, which were independently validated with the testing set. The nomogram was constructed to estimate the probability of transition to MCI at 5-/7-/10-year. The nomogram’s accuracy was assessed using calibration curves and concordance index (C-index), and clinical utility was evaluated through decision curve analysis.
RESULTS: The model incorporating age, brain volume, functional, and radiomics features demonstrated the highest predictive performance for SCD progression in training (C-index: 0.962; 95 % CI: 0.95–0.98) and testing (C-index: 0.911; 95 % CI: 0.861–0.968) sets. A nomogram comprising 10 predictors was constructed to estimate individualized risk of progression to MCI at 5-/7-/10-year. The calibration curve showed good agreement between predicted and observed values. Decision curve analysis demonstrated the nomogram had substantial clinical value.
CONCLUSIONS: This multivariate model and nomogram could accurately predict the individual progression from SCD to MCI.
CITATION:
Xingyan Le ; Junbang Feng ; Xiaoli Yu ; Yuyin Wang ; Qingbiao Zhang ; Yuwei Xia ; Feng Shi ; Chuanming Li (2025): Individualized prediction of transition from subjective cognitive decline to mild cognitive impairment based on multimodal MRI: a 10-year follow-up study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100462
LONGITUDINAL CHANGES IN SUBCORTICAL FUNCTIONAL CONNECTIVITY DURING ALZHEIMER’S DISEASE PROGRESSION
Sunghun Kim, Sewook Oh, Hyunjin Park, Bo-yong Park
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryHuman cognition and behavior rely on the integration of large-scale neural networks that connect the cerebral cortex and subcortical structures. Emerging evidence suggests that alterations in the functional connectivity (FC) between the cortical and subcortical regions in Alzheimer’s disease (AD) may influence the onset and progression of both cognitive and noncognitive symptoms at the group level. However, an individualized and longitudinal framework to capture deviations in subcortico-cortical FC from normative brain aging remains underexplored. We addressed this gap by leveraging large-scale longitudinal neuroimaging datasets and applying a normative modeling approach to characterize subcortical FC trajectories across the adult lifespan. First, we quantified individual deviations in the subcortical FC in individuals with cognitive impairment (CI) relative to a normative aging group using centile scores and tracked longitudinal changes across multiple follow-ups. We examined the relationship between changes in subcortical FC and clinical measures of cognitive function, including episodic memory, executive function, and language. Our findings revealed widespread decreases in the subcortical FC in individuals with CI, except in the limbic network, which diverged from the patterns observed in normal aging. These alterations are significantly associated with a decline in memory and executive functions. Collectively, our results may advance our understanding of AD-related connectopathy and provide a direction for profiling individualized longitudinal FC changes in individuals with CI. Furthermore, our results could inform individualized prognosis and targeted interventions.
CITATION:
Sunghun Kim ; Sewook Oh ; Hyunjin Park ; Bo-yong Park (2025): Longitudinal changes in subcortical functional connectivity during Alzheimer’s disease progression. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100463
THE ASSOCIATION OF ESTIMATED GLUCOSE DISPOSAL RATE WITH WHITE MATTER HYPERINTENSITIES: A LARGE PROSPECTIVE COHORT STUDY
Han Wang, Zhi-Ming Li, Ben-Bo Xiong, Zi-Jie Wang, Yi Qian, Xiao Hu, Shan-Yu Zhang, Chu Chen, Tian-Nan Yang, Qi Li
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND AND OBJECTIVES: Estimated glucose disposal rate (eGDR) is a novel and reliable marker of insulin resistance (IR), yet its association with white matter hyperintensities (WMH) remains unclear. This study investigates the relationship between eGDR and WMH in a cohort from the UK Biobank.
METHODS: We included 34,789 participants without a history of stroke or dementia at baseline. WMH volume was estimated from T2-FLAIR brain magnetic resonance imaging (MRI) scans acquired in 2014, normalized to intracranial volume, and log-transformed. Multiple linear regression models were used to examine the association between eGDR and WMH volume. Additionally, restricted cubic spline (RCS) analysis was employed to explore the dose-response relationship between eGDR and WMH volume.
RESULTS: Each 1-SD increase in eGDR was significantly associated with a reduction in WMH volume (β = -0.057; 95% CI: -0.062 to -0.051; p < 0.001). Compared to participants in the lowest eGDR quartile (Q1), those in quartiles Q2, Q3, and Q4 exhibited progressively lower WMH volumes, with β coefficients of -0.068 (95% CI: -0.097 to -0.039), -0.199 (95% CI: -0.228 to -0.169), and -0.295 (95% CI: -0.330 to -0.259), respectively (p for trend < 0.001). RCS analysis demonstrated a significant linear inverse relationship between eGDR and WMH volume (p for nonlinearity > 0.05). Subgroup analyses indicated consistent associations across most predefined groups.
CONCLUSION: Lower eGDR levels are associated with a greater burden of WMH, suggesting that eGDR may serve as a potential marker for predicting WMH burden in future clinical practice.
CITATION:
Han Wang ; Zhi-Ming Li ; Ben-Bo Xiong ; Zi-Jie Wang ; Yi Qian ; Xiao Hu ; Shan-Yu Zhang ; Chu Chen ; Tian-Nan Yang ; Qi Li (2025): The association of estimated glucose disposal rate with white matter hyperintensities: A large prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100464
ASSOCIATION BETWEEN PLANT-BASED DIETS AND INCIDENT DEMENTIA: RESULTS FROM PROSPECTIVE COHORT STUDIES AND A META-ANALYSIS
Jie Shen, Hui Chen, Yiying Gong, Yuhui Huang, Minyu Wu, Yuxuan Gu, Tian Wang, Luigi Fontana, Shuang Rong, Shujiao Qian, Maurizio Tonetti, Xiaoran Liu, Changzheng Yuan
J Prev Alz Dis 2026;2(13)
Show summaryHide summaryBACKGROUND: Plant-based diets are increasingly advocated for their health benefits, yet their associations with dementia risk remains inconclusive. We evaluated the associations between plant-based dietary patterns and dementia risk across three prospective cohorts and a meta-analysis.
METHODS: Cohort analyses included the Health and Retirement Study (HRS; N = 6642), Framingham Heart Study Offspring cohort (FOS; N = 3045), and Whitehall II study (WHII; N = 8219). Participants were aged ≥45 years and free of dementia at baseline. The overall plant-based diet index (PDI), healthful plant-based diet index (hPDI) and unhealthful plant-based diet index (uPDI) were calculated from validated food frequency questionnaires. Further, a meta-analysis was conducted incorporating data from 5 cohort studies (N = 207,981).
RESULTS: In the cohort analyses, 891 incident dementia cases were identified over 166,762 person-years. In multivariable-adjusted Cox proportional hazard models, higher scores in PDI and hPDI were associated with lower risk of dementia (highest vs. lowest tertile: pooled HR for PDI = 0.70, 95% CI, 0.53–0.92, p for trend <0.001; pooled HR for hPDI = 0.71, 0.48–1.06, p for trend = 0.03). Main contributors to lower risk were higher intake of vegetables, nuts, tea or coffee, and legumes. Conversely, higher uPDI was associated with higher dementia risk (highest vs. lowest tertile: pooled HR = 1.42, 1.19–1.70, p for trend <0.001). In the meta-analysis, individuals in the highest hPDI tertile had 21% lower dementia risk, and those in the highest uPDI tertile had 24% higher risk.
CONCLUSIONS: The healthful plant-based diet was associated with lower risk of dementia, whereas the unhealthful plant-based diet was linked to higher risk. These findings support recommendations to adopt diets rich in healthy plant foods for dementia prevention.
CITATION:
Jie Shen ; Hui Chen ; Yiying Gong ; Yuhui Huang ; Minyu Wu ; Yuxuan Gu ; Tian Wang ; Luigi Fontana ; Shuang Rong ; Shujiao Qian ; Maurizio Tonetti ; Xiaoran Liu ; Changzheng Yuan (2025): Association between plant-based diets and incident dementia: results from prospective cohort studies and a meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100457
LETTER TO THE EDITOR : ADVANCING NUTRITIONAL STRATEGIES FOR BRAIN HEALTH: RECONCILING EPIDEMIOLOGIC FINDINGS WITH CLINICAL APPLICABILITY
Hui Guo, Xiongfei Zhao
J Prev Alz Dis 2026;2(13)
Show summaryHide summary
CITATION:
Hui Guo ; Xiongfei Zhao (2025): Letter to the Editor: Advancing nutritional strategies for brain health: Reconciling epidemiologic findings with clinical applicability. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2025.100466