04/2026 journal articles
EDITORIAL: REMOTE OUTCOME MEASURES IN ALZHEIMER\'S DISEASE CLINICAL TRIALS: A CALL TO ACTION
Gustavo A. Jimenez-Maggiora
J Prev Alz Dis 2026;4(13)
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CITATION:
Gustavo A. Jimenez-Maggiora (2026): Editorial: Remote outcome measures in Alzheimer's disease clinical trials: A call to action. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100528
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
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: 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
LECANEMAB FOR TREATMENT OF INDIVIDUALS WITH EARLY ALZHEIMER’S DISEASE (AD) WHO ARE APOLIPOPROTEIN E Ε4 (APOE Ε4) NON-CARRIERS OR HETEROZYGOTES
Richard Perry, Christopher Kipps, Maria Eugenia Soto Martín, Marco Bozzali, Giancarlo Logroscino, Sarah Trafford, Shobha Dhadda, Michio Kanekiyo, Amanda Goodwin, Mark Hodgkinson, Steven Hersch, Michael Irizarry, Lynn Kramer, Lutz Froelich
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Lecanemab, an antibody directed at Aβ-protofibrils and plaque, showed meaningful delay in disease progression and biological effects consistent with disease modification in the phase 3 Clarity AD trial.
OBJECTIVE: The objective of this paper is to present efficacy and safety results in ApoE ε4 non-carriers or heterozygotes population of Clarity AD.
DESIGN: Clarity AD is an 18-month, randomized study (core) in participants with early AD, with an open-label extension phase (OLE) phase.
SETTING: Academic and clinical centers.
PARTICIPANTS: All eligible ApoE ε4 participants were randomized 1:1 across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly); the results presented herein are for the ApoE4 heterozygote or non-carrier participants.
MEASUREMENTS: Endpoints included change from baseline at 18 months in the global cognitive and functional scale, CDR-SB, amyloid positron emission tomography (PET), Alzheimer’s Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14), Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL), and health-related quality-of-life (HRQoL) assessments. Amyloid imaging related abnormalities (ARIA) occurrence was monitored throughout the study by central reading of magnetic resonance imaging. Following 18 months treatment in the Core, eligible participants transitioned to the OLE where they received open-label lecanemab. Clinical outcomes (CDR-SB, ADAS-Cog14, and ADCS-MCI-ADL) were evaluated by examining ‘delayed start’ (core:placebo followed by OLE:lecanemab) and ‘early start’ (core:lecanemab followed by OLE:lecanemab) cohorts as well as natural history cohorts. Time to progression to next stage of AD was also evaluated through 36 months.
RESULTS: 1795 participants with early AD were enrolled in Clarity AD, of which 1521 were ApoE ε4 heterozygotes or non-carriers (85 %). Lecanemab significantly reduced clinical decline on CDR-SB at 18 months compared to placebo in the ApoEε4 heterozygotes or non-carriers subgroup. Amyloid PET, ADAS-Cog14, ADCS-MCI-ADL, and HRQoL results were consistent with the CDR-SB findings. In the analysis subgroup, the most common adverse reactions for lecanemab were infusion-related reactions (26 %), ARIA-H (13 %), fall (11 %), headache (11 %), and ARIA-E (9 %). In the OLE, lecanemab-treated participants continued to accrue benefit in CDR-SB through 36 months, with continued separation through 36 months relative to the ADNI natural history cohort. Delayed start results follow a parallel trajectory relative to early start results, but do not catch up, confirming a disease modifying effect and reflecting importance of early treatment initiation. Results were similar for ADAS-Cog14 and ADCS-MCI-ADL. Lecanemab reduced the risk of progression to next stage of AD by 28 % on lecanemab as compared to the ADNI natural history cohort.
CONCLUSION: In the ApoE ε4 heterozygotes or non-carrier subgroup of Clarity AD, lecanemab slowed decline in disease progression and reduced markers of amyloid, with expanding benefit over time.
CITATION:
Richard Perry ; Christopher Kipps ; Maria Eugenia Soto Martín ; Marco Bozzali ; Giancarlo Logroscino ; Sarah Trafford ; Shobha Dhadda ; Michio Kanekiyo ; Amanda Goodwin ; Mark Hodgkinson ; Steven Hersch ; Michael Irizarry ; Lynn Kramer ; Lutz Froelich (2026): Lecanemab for treatment of individuals with early Alzheimer’s Disease (AD) who are apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100507
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
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryINTRODUCTION: 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
PREDICTING COGNITIVE DECLINE: COMPARATIVE ANALYSIS OF ANU-ADRI, CAIDE, COGDRISK, LIBRA, LIBRA2, UKBDRS AND LANCET BASED DEMENTIA RISK SCORES IN THE HUNT STUDY
Josephine Stubs, Geir Selbæk, Bjørn Heine Strand, Gill Livingston, Kaarin J. Anstey, Kay Deckers, Mika Kivimäki, Steinar Krokstad, Fiona E. Mathews, Ellen Melbye Langballe
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryOBJECTIVE: To evaluate and compare the predictive value of eight dementia risk scores for late-life cognitive function and cognitive decline; ANU-ADRI, CAIDE, CogDrisk, LIBRA, LIBRA2, UKBDRS(-APOE), and a Lancet commission-based risk score.
METHODS: Using Norwegian Trøndelag Health Study (HUNT) data, we calculated risk scores from lifestyle and health data of 7221 dementia-free participants (mean age: 76.8 years, 54.1% female) collected in HUNT3 (2006–2008). Cognitive function was assessed using the Montreal Cognitive Assessment scale (MoCA) 11 years later in HUNT4 70+, and reassessed in 4716 participants 4 years thereafter. Associations between continuous risk scores or risk score tertiles, cognition and cognitive decline were examined using linear mixed-effects models. Logistic regression models were used to test associations between risk scores and a ≥ 3-point decline in MoCA scores.
RESULTS: All risk scores were significantly associated with cognitive function and cognitive decline. Associations with cognitive function ranged from UKBDRS β per 1SD=-1.61(95%CI:-1.72,-1.51) to CAIDE (β=-0.74;95%CI:-0.82,-0.67), and with yearly cognitive decline from Lancet (β=-0.23;95%CI:-0.27,-0.18) to CAIDE (β=-0.04;95%CI:-0.07,-0.02). High-low risk group differences in cognitive function were largest for CogDrisk (β=-3.04;95%CI:-3.27,-2.81), LIBRA (β=-3.04;95%CI:-3.27,-2.80) and lowest for CAIDE (β=-1.65;95%CI:-1.86,-1.44). High-risk groups showed the steepest decline for UKBDRS-APOE (β=-0.43;95%CI:-0.52,-0.34), Lancet (β=-0.39;95%CI:-0.48,-0.30), and LIBRA (β=-0.38;95%CI:-0.47,-0.28). All scores predicted ≥3-point decline modestly: AUCs were highest for UKBDRS (AUC=0.61;95%CI:0.60,0.63), UKBDRS-APOE (0.61;95%CI:0.60,0.63), CogDrisk (0.60;95%CI:0.58,0.62), and Lancet (0.60;95%CI:0.58,0.61), but none outperformed a model including age and education alone (0.61;95%CI:0.60,0.63).
CONCLUSION: Risk scores captured meaningful gradients in cognition and decline but offered limited discriminatory accuracy beyond demographics, supporting their use for prevention-oriented risk profiling rather than prediction.
CITATION:
Josephine Stubs ; Geir Selbæk ; Bjørn Heine Strand ; Gill Livingston ; Kaarin J. Anstey ; Kay Deckers ; Mika Kivimäki ; Steinar Krokstad ; Fiona E. Mathews ; Ellen Melbye Langballe (2026): Predicting cognitive decline: Comparative analysis of ANU-ADRI, CAIDE, CogDrisk, LIBRA, LIBRA2, UKBDRS and Lancet based dementia risk scores in the HUNT study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100524
ESTIMATED PREVALENCE OF UNDERDIAGNOSED DEMENTIA IN A MULTIETHNIC COMMUNITY-BASED STUDY
Lydia Trudel, Joseph Therriault, Arthur C. Macedo, Meredith N. Braskie, Karin L. Meeker, Arthur W. Toga, Serge Gauthier, Paolo Vitali, Sid E. O’Bryant, Pedro Rosa-Neto
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryDementia frequently goes undetected in community settings, particularly among socially disadvantaged populations. Here, we estimated the prevalence of underdiagnosed dementia across diverse sociodemographic determinants of health in the Health and Aging Brain Study–Health Disparities (HABS-HD), a community-based cohort of adults recruited through community outreach in Fort Worth, Texas. We estimated age-specific probabilities of underdiagnosis using Poisson regression models with a log link, including age and sex as covariates. Robust (sandwich) variance estimators were used to obtain standard errors and 95% confidence intervals (CI). Group differences or trends for continuous measures were assessed using robust variance estimates. The prevalence of underdiagnosed dementia was higher among individuals without physician access (98.1% vs. 78.1%, p<.0001), non-English speakers (97.9% vs. 76.8%, p<.0001), and the uninsured (91.5% vs. 79.5%, p=.03). Black and Hispanic participants also showed higher prevalence (85.8% and 90.9%) compared to non-Hispanic White participants (64.9%; p=.02 and p=.002, respectively). Each additional year of education was associated with a 2.5% lower risk of underdiagnosis (p<.0001). No differences were observed by sex, marital status, income or social support. Our results highlight that several sociodemographic factors contribute to the likelihood of living with undiagnosed dementia.
CITATION:
Lydia Trudel ; Joseph Therriault ; Arthur C. Macedo ; Meredith N. Braskie ; Karin L. Meeker ; Arthur W. Toga ; Serge Gauthier ; Paolo Vitali ; Sid E. O’Bryant ; Pedro Rosa-Neto (2026): Estimated prevalence of underdiagnosed dementia in a multiethnic community-based study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100510
LONGITUDINAL SUBCORTICAL VOLUME CHANGES AND THEIR CORRELATIONS WITH MULTIPLE PET AND FLUID BIOMARKERS IN DOMINANTLY INHERITED ALZHEIMER’S DISEASE
IL Han Choo, Hoyoung Park, Brian A. Gordon, Randall J. Bateman, the Dominantly Inherited Alzheimer Network
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Alzheimer's disease postmortem studies demonstrate that amyloid plaques and neurofibrillary tangles are present in subcortical regions.
OBJECTIVE: To investigate longitudinal subcortical structural changes in autosomal dominant Alzheimer’s disease in relation to multiple PET and fluid biomarkers.
DESIGN: Dominantly Inherited Alzheimer’s Network (DIAN) Observational study.
SETTING: Multicenter study.
PARTICIPANTS: Participants were identified as mutation-carriers of pathologic variants in presenilin-1, presenilin-2, or amyloid precursor protein and as non-carriers from the same families as the mutation-carriers. They underwent baseline and 2 and more times longitudinal follow-up assessments of multiple biomarkers
MEASUREMENTS: Participants underwent structural MRI, ¹¹C-Pittsburgh Compound B PET, ¹⁸F-fluorodeoxyglucose PET, and CSF and plasma assessments. Rates of biomarker change as a function of estimated years to symptom onset were estimated using multivariate linear mixed-effects models, and longitudinal associations between subcortical atrophy and multiple biomarkers were evaluated.
RESULTS: A total of 601 participants completed one or more clinical evaluations, with up to eight annual visits. Mutation carriers showed significantly greater longitudinal atrophy in the left amygdala, bilateral thalamus, putamen, nucleus accumbens, and hippocampus compared with non-carriers (Bonferroni-corrected p < 0.05). The earliest divergence was observed 13.2 years before the expected symptom onset in the right nucleus accumbens, following amyloid-β (Aβ) accumulation in the right thalamus that began 23.8 years before onset. Among carriers, atrophy in the right thalamus, bilateral putamen, and bilateral nucleus accumbens was significantly associated with region-specific or cortical Aβ accumulation, as well as with CSF Aβ42, Aβ42/Aβ40 ratio, total tau, and phosphorylated tau (Bonferroni-corrected p < 0.05).
CONCLUSIONS: The present findings may provide a unique and well-characterized model for investigating the temporal ordering of Alzheimer’s disease biomarkers.
CITATION:
IL Han Choo ; Hoyoung Park ; Brian A. Gordon ; Randall J. Bateman ; the Dominantly Inherited Alzheimer Network (2026): Longitudinal subcortical volume changes and their correlations with multiple PET and fluid biomarkers in dominantly inherited Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100513
VASCULAR STIFFNESS PREDICTS PLASMA MARKERS OF NEURODEGENERATION AMONG OLDER AFRICAN AMERICANS
Miray Budak, Kevin S. Heffernan, Victoria Paruzel, Soodeh Moallemian, Bernadette A. Fausto, Nicholas Ashton, Henrik Zetterberg, Fanny M. Elahi, Mark A. Gluck
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Vascular health is a critical and potentially modifiable determinant of Alzheimer’s disease (AD) risk, yet its contribution to early neurodegenerative processes remains incompletely understood, particularly among African Americans, who experience a disproportionate AD burden. Estimated pulse wave velocity (ePWV), derived from age and blood pressure, provides a scalable index of vascular stiffness.
OBJECTIVES: To examine associations between vascular stiffness and plasma biomarkers of AD-related neurodegeneration in older African Americans.
DESIGN: Cross-sectional observational study.
SETTING: Community-based aging cohort study conducted at an academic research center.
PARTICIPANTS: A total of 145 cognitively unimpaired older African Americans (mean age=71.18±6.83 years; 110 women).
MEASUREMENTS: ePWV was calculated using validated equations based on age and blood pressure. Plasma biomarkers included phosphorylated tau217 (p-tau217; N=145), phosphorylated tau231 (p-tau231; N=126), glial fibrillary acidic protein (GFAP; N=126), neurofilament light chain (NfL; N=126), and amyloid-β42/40 ratio (Aβ42/40; N=126). Multivariable regression models adjusted for sex, education, pulse pressure, waist-to-hip ratio, global cognition, and hypertension status.
RESULTS: Higher ePWV was significantly associated with higher plasma concentrations of p-tau217 (β=0.34, p=.006), GFAP (β=0.55, p<.001), and NfL (β=0.52, p<.001), but not with p-tau231 and Aβ42/40 (p>.05).
CONCLUSIONS: Greater vascular stiffness, indexed by elevated ePWV, was associated with circulating markers of tau-related neurodegeneration, astrocytic activation, and axonal injury in cognitively unimpaired older African Americans. The absence of association with p-tau231 and Aβ42/40 suggests preferential effects on neurovascular damage and later tau-related processes, but no primary effect on biomarkers related to Aβ pathology, still highlighting vascular health as a modifiable target for AD prevention.
CITATION:
Miray Budak ; Kevin S. Heffernan ; Victoria Paruzel ; Soodeh Moallemian ; Bernadette A. Fausto ; Nicholas Ashton ; Henrik Zetterberg ; Fanny M. Elahi ; Mark A. Gluck (2026): Vascular stiffness predicts plasma markers of neurodegeneration among older African Americans. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100523
EXPERIMENTAL AND TRANSLATIONAL MODELS OF ALZHEIMER’S DISEASE: FROM NEURODEGENERATION TO NOVEL THERAPEUTIC INSIGHTS
Nadeemullah Khan, Somnath De, Suhasini Boddu, Navya Pravala
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryNeurodegeneration 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
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
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND 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
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
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND 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
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
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: 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
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
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: 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
ASSOCIATION BETWEEN MRI INDICATORS OF THE GLYMPHATIC SYSTEM AND COGNITION IN HIGH-RISK POPULATIONS FOR ALZHEIMER\'S DISEASE
Li Jiang, Ling Zhang, Shu-Xian Wu, Qin-Qin Zhu, Wei Wang, Jia-Wei Gao, Yi Zhu, Shui Tian, Ming Qi
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Using the Diffusion Tensor Image Analysis Along the Perivascular Space (ALPS) method and perivascular space (PVS) burden to study glymphatic function in high-risk Alzheimer's disease (AD) populations, this research investigates the correlation between ALPS index and PVS volume with cognitive function respectively.
METHODS: This study enrolled 126 participants, including 21 cognitively unimpaired (CU) individuals, 68 with subjective cognitive decline (SCD), and 37 with mild cognitive impairment (MCI). All participants underwent MRI and cognitive assessments. MRI measures, including the PVS burden and the ALPS index, were compared across SCD, MCI, and CU groups. Additionally, correlations among the ALPS index, PVS burden, and cognitive scales were analyzed.
RESULTS: The PVS in the basal ganglia volume fraction (PVSVF-BG) in patients with MCI was significantly larger than the fraction in CUs (p < 0.05) and a higher PVSVF-BG was associated with poorer performance on the Trail Making Test A (TMTA) (r = 0.29, p < 0.05). Compared with the CU and SCD groups, patients with MCI exhibited a significantly lower ALPS index in both the left (p < 0.05) and right hemispheres (p < 0.001). Lower whole brain ALPS index in patients with MCI was correlated with worse performance in the Auditory Verbal Learning Test(AVLT) (N4, r = 0.33, p < 0.05; N7, r = 0.56, p < 0.001).
CONCLUSIONS: An increased PVS burden and a decreased ALPS index can be observed in the preclinical stage of AD, which may suggest impaired glymphatic system function. These impairments were further correlated with worse cognitive performance in terms of attention in SCD and memory in MCI.
CITATION:
Li Jiang ; Ling Zhang ; Shu-Xian Wu ; Qin-Qin Zhu ; Wei Wang ; Jia-Wei Gao ; Yi Zhu ; Shui Tian ; Ming Qi (2026): Association between MRI indicators of the glymphatic system and cognition in high-risk populations for Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100504
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
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND 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
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
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: 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
THE ROLE OF LIPIDS IN MEDIATING THE EFFECTS OF IMMUNE CELLS ON ALZHEIMER’S DISEASE RISK: A NETWORK MENDELIAN RANDOMIZATION STUDY
Xinyu Yang, Jingjing Jiang, Wenjing Li, Rui Pan, Yanjie Li
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Observational studies have shown associations between immune cells, lipids, and Alzheimer’s disease (AD), but their specific causal relationships and the mediating role of lipids remain unclear.
METHODS: Within a network Mendelian randomization (MR) framework, we first applied two-sample univariable MR to assess the causal effects of immune cells and lipids on AD. Then, multivariable MR was used in mediation analyses to determine whether lipids mediate the effects of immune cells on AD. Finally, reverse MR analyses were performed to minimize potential bias from reverse causation. The inverse variance weighted method was used as the primary estimator.
RESULTS: The analysis revealed that elevated levels of CD33 on CD33dim HLA DR+ CD11b+ and CD33 on CD33dim HLA DR+ CD11b- were associated with an increased risk of AD. Mediation analysis further indicated that polyunsaturated fatty acids are protective lipid metabolites for AD and partially mediate the effects of the aforementioned immune cells on AD, with mediation proportions of 3.70 % and 3.67 %, respectively.
CONCLUSION: This study provides new insights into how immune cells may influence AD pathogenesis through lipid metabolism. It also offers a theoretical basis and potential direction for developing immune–lipid-based strategies for AD prevention and intervention.
CITATION:
Xinyu Yang ; Jingjing Jiang ; Wenjing Li ; Rui Pan ; Yanjie Li (2026): The role of lipids in mediating the effects of immune cells on Alzheimer’s disease risk: A network Mendelian randomization study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100509
DIAGNOSTIC AND PROGNOSTIC UTILITY OF SERUM Β-SYNUCLEIN IN ALZHEIMER’S DISEASE: A LONGITUDINAL COHORT STUDY
Siqi Xie, Yumei Liang, Ting Yang, Dandan Sheng, Lan Ding, Jianping Jia, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Serum β-synuclein is an emerging blood-based biomarker for synaptic integrity in Alzheimer’s disease (AD). However, its comparative performance against the established CSF marker neurogranin and its prognostic utility for longitudinal disease progression remain to be fully characterized.
METHOD: We analyzed 475 participants from the Alzheimer’s Disease Neuroimaging Initiative. We compared serum β-synuclein and CSF neurogranin using receiver operating characteristic analysis and Cox proportional hazards models. We also assessed the cross-sectional associations of both biomarkers with cognitive and neuroimaging markers using linear regression. Linear mixed-effects models were applied to determine if baseline serum β-synuclein levels and longitudinal rate of change predicted disease progression. Finally, the trajectory of serum β-synuclein was modeled across the AD continuum.
RESULTS: Serum β-synuclein distinguished clinical AD dementia from controls with high accuracy (AUC = 0.84). Cross-sectionally, it exhibited robust associations with cognitive deficits and neuroimaging markers, comparable to or exceeding those of CSF neurogranin. Higher baseline serum β-synuclein, but not CSF neurogranin, significantly predicted the risk of conversion to dementia (hazard ratio = 1.83). Longitudinally, both elevated baseline levels and faster rates of increase in serum β-synuclein predicted accelerated cognitive decline and neurodegeneration, independent of baseline amyloid or tau pathology. Trajectory analysis revealed that serum β-synuclein levels accelerated significantly over time specifically in individuals with concurrent amyloid and tau pathology.
DISCUSSION: Serum β-synuclein serves as a robust prognostic biomarker for AD, demonstrating diagnostic accuracy for clinical dementia and superior predictive utility for disease conversion compared to CSF neurogranin. Its ability to track synaptic degeneration independent of core proteinopathies highlights its potential as a dynamic outcome measure for monitoring disease progression in clinical trials.
CITATION:
Siqi Xie ; Yumei Liang ; Ting Yang ; Dandan Sheng ; Lan Ding ; Jianping Jia ; Alzheimer’s Disease Neuroimaging Initiative (2026): Diagnostic and prognostic utility of serum β-synuclein in Alzheimer’s disease: a longitudinal cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100514
HEALTHY LIFESTYLE AND ALZHEIMER’S DISEASE IN INDIVIDUALS WITH HYPERLIPIDEMIA: A PROSPECTIVE COHORT STUDY
Danyang Sun, Linling Yu, Chenqi Liao, Yuzhong Xu, Wei Liu, Xiong Wang
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Whether healthy lifestyle behaviors are associated with Alzheimer’s disease (AD) risk among individuals with hyperlipidemia remains unclear.
METHODS: We analyzed 241,642 dementia-free participants from the UK Biobank. A weighted lifestyle score (0–7) was derived from seven factors and categorized into five tiers. Hyperlipidemia was defined as lipid-lowering medication use or LDL-cholesterol ≥ 4.0 mmol/L. Cox regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs).
RESULTS: Over a median follow-up of 14.5 years, 1728 AD cases occurred, including 977 cases among 104,082 individuals with hyperlipidemia. Compared with the intermediate tier, unhealthy lifestyle was associated with elevated AD risk (HR: 1.17; 95% CI: 1.02–1.35), while healtshy and very healthy tiers were associated with progressively lower risk (HR=0.85 and 0.74, respectively). These associations were evident among individuals with hyperlipidemia, but not statistically significant among those without hyperlipidemia.
CONCLUSIONS: Healthy lifestyle patterns were associated with lower AD risk among individuals with hyperlipidemia, with greater risk reductions observed for healthier lifestyle tiers.
CITATION:
Danyang Sun ; Linling Yu ; Chenqi Liao ; Yuzhong Xu ; Wei Liu ; Xiong Wang (2026): Healthy lifestyle and Alzheimer’s disease in individuals with hyperlipidemia: A prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100520
ASSOCIATIONS BETWEEN PLANT-BASED DIETARY PATTERNS AND RISKS OF COGNITIVE IMPAIRMENT AND DEMENTIA: A SYSTEMATIC REVIEW AND DOSE-RESPONSE META-ANALYSIS
Jui-Hsiu Tsai, Tou-Yuan Tsai, Hua Li, Cheng-Yu Wang, Yu-Kang Tu, Huei-Kai Huang, Hsin Ma, Yu-Lin Hsieh, Chuan-Sheng Hung, Shih-Chieh Shao, Eric H Chou, Chin-Lon Lin, Ming-Nan Lin
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Evidence remains inconclusive regarding plant-based diets preventing cognitive impairment and dementia, as certain plant-based foods, including refined carbohydrates, sweets, sugar-sweetened beverages, and trans fats, may increase dementia risk.
OBJECTIVES: To quantitatively synthesize prospective cohort studies on associations between adherence to plant-based diets and the risks of cognitive impairment and dementia.
DESIGN: Systematic review and meta-analysis. This study adhered to the PRISMA guidelines and was registered on PROSPERO (No: CRD42024501334).
SETTING: Studies published until December 2025 were systematically identified using AgeLine, CINAHL, Embase, MEDLINE, PsycINFO, Scopus, and Web of Science.
PARTICIPANTS: The study population comprised adults aged ≥ 20 years with no cognitive impairment at baseline.
INTERVENTION: Studies were enrolled if the participants (1) assessed dietary patterns characterized by higher plant-based food consumption and decreased or ceased consumption of animal-based foods or (2) used established dietary indices, including overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI).
MEASUREMENTS: Data extraction, risk of bias assessment, and the GRADE approach for assessing certainty of evidence were performed independently by three reviewers. A random-effects model with restricted maximum likelihood was used to calculate pooled risk ratios and 95% confidence intervals. The dose-response meta-analysis used two-stage dose-response regression.
RESULTS: The meta-analysis based on seven studies (number of participants: 221,380; number of cases of incident cognitive impairment and dementia: 5668) indicated that participants with greater adherence to plant-based diets had significantly lower risks of cognitive impairment and dementia (pooled risk ratio, 0.74; 95% confidence interval, 0.56–0.97; I2 = 92.3%) than those with lower adherence. Dose-response relationships modeled using restricted cubic splines indicated that overall PDI and hPDI were negatively associated with risks of cognitive impairment and dementia, whereas uPDI was significantly positively associated with these risks.
CONCLUSIONS: This meta-analysis suggests that adherence to plant-based diets, particularly those rich in healthful plant foods, may be associated with a lower risk of cognitive impairment and dementia. However, given the residual heterogeneity and the inherent limitations of observational study designs, large randomised controlled trials are warranted to establish causality.
CITATION:
Jui-Hsiu Tsai ; Tou-Yuan Tsai ; Hua Li ; Cheng-Yu Wang ; Yu-Kang Tu ; Huei-Kai Huang ; Hsin Ma ; Yu-Lin Hsieh ; Chuan-Sheng Hung ; Shih-Chieh Shao ; Eric H Chou ; Chin-Lon Lin ; Ming-Nan Lin (2026): Associations between plant-based dietary patterns and risks of cognitive impairment and dementia: A systematic review and dose-response meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100521
LIFESTYLE FACTORS AND DNA METHYLATION-BASED AGING CLOCKS: CROSS-SECTIONAL AND LONGITUDINAL ASSOCIATIONS IN THE SINGAPORE DIET AND HEALTHY AGING COHORT
Jiatong Shan, Jian Hua Tay, Kaisy Xinhong Ye, Jiuyu Guo, Luwen Cao, Yan Zeng, Tih-Shih Lee, Kua Ee Heok, Brian K. Kennedy, Andrea B. Maier, Lei Feng
J Prev Alz Dis 2026;4(13)
Show summaryHide summaryBACKGROUND: Lifestyle factors play a critical role in healthy aging, yet their relationships with aging biomarkers remain insufficiently characterized, particularly in Asian populations. This study aimed to examine the cross-sectional and longitudinal associations between 15 modifiable lifestyle factors and two DNA methylation (DNAm) clocks (GrimAge acceleration [AgeDev] and DunedinPACE) in a cohort of older Asian adults.
METHODS: We conducted a cross-sectional analysis of 631 participants (median age 70.0 years; 72.6% female) and a longitudinal analysis of 114 participants (mean follow-up 3.96 years) from the Singapore Diet and Healthy Aging (DaHA) cohort. Lifestyle exposures were assessed using validated self-administered questionnaires. Peripheral blood DNAm profiles were generated using the Illumina MethylationEPIC array. Multivariable linear regression models were applied to evaluate associations between lifestyle factors and DNAm clocks, adjusting for sociodemographic covariates, health status, and immune cell-type proportions.
RESULTS: In cross-sectional analyses, smoking history showed robust positive associations with accelerated epigenetic aging (GrimAge AgeDev: β = 1.45, 95% CI 1.13–1.77, p < 0.0001; DunedinPACE: β = 0.63, 95% CI 0.22–1.05, p = 0.003). Conversely, weekly physical activity was associated with slower aging (GrimAge AgeDev: β = –0.22, 95% CI –0.40 to –0.04, p = 0.02), as was daily engagement in cognitively stimulating activities (GrimAge AgeDev: β = –0.16, 95% CI –0.31 to –0.01, p = 0.04). Weekly feelings of stress were initially associated with greater GrimAge AgeDev, but this relationship was attenuated after full adjustment. No significant longitudinal associations were detected, which may reflect limited statistical power and the stability of long-standing lifestyle behaviors over the follow-up period.
CONCLUSIONS: These findings highlight significant cross-sectional associations between key modifiable lifestyle factors, particularly smoking, physical activity, and cognitive engagement, and epigenetic aging in an older Asian cohort. The results suggest that interventions targeting these behaviors may modulate the pace of biological aging. The absence of significant longitudinal associations underscores the need for larger prospective studies with longer follow-up and continued validation of epigenetic clocks in diverse populations to confirm these relationships over time.
CITATION:
Jiatong Shan ; Jian Hua Tay ; Kaisy Xinhong Ye ; Jiuyu Guo ; Luwen Cao ; Yan Zeng ; Tih-Shih Lee ; Kua Ee Heok ; Brian K. Kennedy ; Andrea B. Maier ; Lei Feng (2026): Lifestyle factors and DNA methylation-based aging clocks: cross-sectional and longitudinal associations in the Singapore diet and healthy aging cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100522
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
J Prev Alz Dis 2026;4(13)
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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
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
J Prev Alz Dis 2026;4(13)
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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
LETTER TO THE EDITOR : THE FUTURE OF HRT/MHT AND ALZHEIMER’S DISEASE RISK, ONSET AND PROGRESSION
Edwin D. Lephart, Dawson W. Hedges, Frederick Naftolin, Zoe D. Draelos
J Prev Alz Dis 2026;4(13)
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CITATION:
Edwin D. Lephart ; Dawson W. Hedges ; Frederick Naftolin ; Zoe D. Draelos (2026): Letter to the Editor: The future of HRT/MHT and Alzheimer’s disease risk, onset and progression. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100508
LETTER TO THE EDITOR : LONG-TERM EXTENSION DATA DO NOT ROBUSTLY SUPPORT CLINICAL DISEASE COURSE MODIFICATION WITH DONANEMAB
Jemma Hazan, Kathy Y. Liu, Robert Howard
J Prev Alz Dis 2026;4(13)
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CITATION:
Jemma Hazan ; Kathy Y. Liu ; Robert Howard (2026): Letter to the Editor: Long-term extension data do not robustly support clinical disease course modification with donanemab. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100511
LETTER TO THE EDITOR: LONG-TERM TREATMENT OF EARLY ALZHEIMER’S DISEASE WITH DONANEMAB
Vincenzo Solfrizzi, Bruno P. Imbimbo
J Prev Alz Dis 2026;4(13)
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CITATION:
Vincenzo Solfrizzi ; Bruno P. Imbimbo (2026): Letter to the Editor: Long-term treatment of early Alzheimer’s disease with donanemab. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100512
CORRIGENDUM TO “LECANEMAB FOR TREATMENT OF INDIVIDUALS WITH EARLY ALZHEIMER’S DISEASE (AD) WHO ARE APOLIPOPROTEIN E Ε4 (APOE Ε4) NON-CARRIERS OR HETEROZYGOTES” [THE JOURNAL OF PREVENTION OF ALZHEIMER\'S DISEASE (2026) 100507]
Richard Perry, Christopher Kipps, Maria Eugenia Soto Martín, Marco Bozzali, Giancarlo Logroscino, Sarah Trafford, Shobha Dhadda, Michio Kanekiyo, Amanda Goodwin, Mark Hodgkinson, Steven Hersch, Michael Irizarry, Lynn Kramer, Lutz Froelich
J Prev Alz Dis 2026;4(13)
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CITATION:
Richard Perry ; Christopher Kipps ; Maria Eugenia Soto Martín ; Marco Bozzali ; Giancarlo Logroscino ; Sarah Trafford ; Shobha Dhadda ; Michio Kanekiyo ; Amanda Goodwin ; Mark Hodgkinson ; Steven Hersch ; Michael Irizarry ; Lynn Kramer ; Lutz Froelich (2026): Corrigendum to “Lecanemab for treatment of individuals with early Alzheimer’s Disease (AD) who are apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes” [The Journal of Prevention of Alzheimer's Disease (2026) 100507]. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100527