Ahead of print articles
PREGNANCY HYPERTENSION IS ASSOCIATED WITH HIGHER P-TAU217 IN HEALTHY MIDLIFE WOMEN
Eu-Leong Yong, Beverly Wen Xin Wong, Darren Yuen Zhang Tan, Liang Shen, Benecia Wan Qing Thia, Joyce Ruifen Chong, Christopher Li-Hsian Chen
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INTRODUCTION: There is very limited knowledge on the relationship between pregnancy hypertension and the occurrence of pre-clinical Alzheimer's disease (AD).
METHODS: Community-dwelling midlife women without dementia were enrolled from well-woman clinics of the National University Hospital, Singapore. Sociodemographic parameters and history of pregnancy hypertension were obtained. Cognition was assessed using the Montreal Cognitive Assessment-Basic tool. Fasted blood samples were stored for batched analysis of renal function, APOE genotyping and p-tau217 levels using Simoa® ALZpath p-tau217 Advantage PLUS (Quanterix, MA, USA). General linear modelling was used to examine the association between pregnancy hypertension and p-tau217.
RESULTS: Among 743 women (mean age 62.9 ± 6.0; range: 50.7 to 76.6 years) enrolled, 68 (9.2%) reported pregnancy hypertension. General linear modelling showed that an older age [mean difference: 0.002 (95% CI: 0.001, 0.003)], mild cognitive impairment [0.016 (0.001, 0.032)], lower BMI [0.068 (0.027, 0.109)], eGFR<60 mL/min/1.73 m2 [0.132 (0.072, 0.193)] and the APOE4 carrier genotype [0.038 (0.018, 0.058)] were independently associated with higher serum p-tau217 levels. History of pregnancy hypertension remained significantly associated with subsequent higher serum p-tau217 [0.040 (0.013, 0.067)], after adjustment for age, mild cognitive impairment, hypertension, BMI, renal function, and APOE4 genotype status.
DISCUSSION: Pregnancy hypertension was associated with AD pathology with mean differences similar to high risk APOE4 carrier genotypes. Information on pregnancy hypertension could help physicians to identify women who might benefit from early p-tau217 screening for Alzheimer’s disease, allowing for early clinical intervention.
CITATION:
Eu-Leong Yong ; Beverly Wen Xin Wong ; Darren Yuen Zhang Tan ; Liang Shen ; Benecia Wan Qing Thia ; Joyce Ruifen Chong ; Christopher Li-Hsian Chen (2025): Pregnancy hypertension is associated with higher p-tau217 in healthy midlife women. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100316
CHOLINERGIC BASAL FOREBRAIN ATROPHY ACCELERATES COGNITIVE DECLINE VIA CORTICAL THINNING: THE MODERATING ROLE OF AMYLOID-Β PATHOLOGY IN PRECLINICAL ALZHEIMER’S DISEASE
Si Cen, Lijuan Wang, Meiling Qiu, Zhongqiang Xu, Li Xu, Rui Bao, Xiaolei Tang, Juanyu Gong, Jinting Wu, Zhiding Shao, Tonghua Zhang, Fan Yang, Wencai Ding, on behalf of the Harvard Aging Brain Study (HABS)
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BACKGROUND: Cholinergic basal forebrain (cBF) atrophy is a critical early marker of neurodegeneration in Alzheimer’s disease (AD). While cBF degeneration is linked to cognitive decline, the role of cortical thinning in this process, especially during the preclinical phase of AD, remains underexplored. Additionally, the impact of amyloid-β (Aβ) pathology on these relationships warrants further examination.
METHODS: We analyzed longitudinal structural MRI and PIB-PET data from 230 cognitively normal older adults enrolled in the Harvard Aging Brain Study, with a mean follow-up of six years. cBF volume and cortical thickness were quantified using FreeSurfer. Cognitive performance was assessed with the Preclinical Alzheimer Cognitive Composite-5 (PACC5). Linear mixed-effects models were used to investigate the longitudinal associations between cBF atrophy, cortical thinning, and cognitive decline. Mediation analyses explored whether cortical thinning mediated the relationship between cBF degeneration and cognitive decline, and the moderating role of Aβ burden was examined.
RESULTS: Progressive cortical thinning in multiple cognition-related regions was significantly associated with cBF atrophy. Mediation analysis revealed that cortical thinning accounted for approximately 44 % of the relationship between cBF degeneration and cognitive decline. These associations were more pronounced in individuals with elevated Aβ, suggesting a synergistic interaction between amyloid pathology and cholinergic system degeneration.
CONCLUSIONS: Our findings suggest that cBF atrophy accelerates cognitive decline through its impact on cortical thinning, with Aβ pathology further exacerbating these effects. These results highlight the potential of cBF and cortical thinning as early biomarkers for preclinical AD and underscore the importance of targeting cholinergic dysfunction in early intervention strategies.
CITATION:
Si Cen ; Lijuan Wang ; Meiling Qiu ; Zhongqiang Xu ; Li Xu ; Rui Bao ; Xiaolei Tang ; Juanyu Gong ; Jinting Wu ; Zhiding Shao ; Tonghua Zhang ; Fan Yang ; Wencai Ding ; on behalf of the Harvard Aging Brain Study (HABS) (2025): Cholinergic basal forebrain atrophy accelerates cognitive decline via cortical thinning: The moderating role of amyloid-β pathology in preclinical Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100315
DIETARY SUGAR INTAKE, GENETIC SUSCEPTIBILITY, AND RISK OF DEMENTIA: A PROSPECTIVE COHORT STUDY
Yu An, Limin Cao, Gang Zheng, Yashu Liu, Honghao Yang, Liangkai Chen, Yuhong Zhao, Xiaopeng Zhang, Yang Xia
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BACKGROUND: Sugar intake has been identified as a risk factor for incident dementia; however, the role of genetic susceptibility in such association remains unclear.
METHODS: This cohort study involved 158,408 participants from the UK Biobank to explore the effect of genetic susceptibility on the association between dietary sugar intake and dementia risk. Data on sugar intake were evaluated using repeated web-based 24-hour dietary recalls. Polygenic risk scores (PRS) for sugar metabolism (Triglyceride Glucose, TyG), gut microbiota, and disease susceptibility (Alzheimer's disease) were generated based on genome-wide association studies.
RESULTS: Over a median follow-up period of 9.94 years, 1,219 dementia cases (0.7%) were documented. There were significant positive dose-response relationships between sugar intake and dementia risk (non-free sugar: HR, 95% CI, Quartile 4 vs. Quartile 1 = 1.26, 1.04–1.52; free sugar: 1.43, 1.20–1.70). Genetic susceptibility, including TyG-PRS, gut microbiota, and disease susceptibility, showed a combined effect on the association between sugar intake and dementia risk. Notably, significant interactions were observed between sugar intake, PRS for Ruminococcaceae UCG-014 and dementia, as well as between free sugar, PRS for Oscillospira and dementia. Participants with lower PRS of Ruminococcaceae UCG-014, or higher PRS of Oscillospira, posed a higher risk of dementia due to sugar intake.
CONCLUSION: Both free and non-free sugar intake are independent risk factors for dementia incidence. The role of genetic susceptibility among such association cannot be ignored. These results underscore the importance of personalized nutritional interventions targeting both dietary habits and genetic risk profiles in dementia prevention strategies.
CITATION:
Yu An ; Limin Cao ; Gang Zheng ; Yashu Liu ; Honghao Yang ; Liangkai Chen ; Yuhong Zhao ; Xiaopeng Zhang ; Yang Xia (2025): Dietary sugar intake, genetic susceptibility, and risk of dementia: A prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100312
DISCLOSURE OF ALZHEIMER’S DISEASE BLOOD-BASED BIOMARKER RESULTS IN A PRIMARY CARE SETTING: OPPORTUNITIES AND CHALLENGES
Corey J. Bolton, Ayda Rostamzadeh, Nathaniel Chin, Nicole R. Fowler, Judith Heidebrink, Annalise Rahman-Fillipiak, Raymond R. Romano III, Lindsay R. Clark, Advisory Group on Risk Evidence Education in Dementia (AGREEDementia)
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Blood-based biomarkers (BBMs) for Alzheimer’s disease (AD) have advanced rapidly and may be a critical tool for broad community-based screening for AD and detection of AD pathology in individuals with cognitive impairment. To meet the impending demand for AD diagnosis, BBMs could be implemented in a primary care setting to maximize accessibility and efficiency. However, this primary care implementation would be associated with numerous challenges, including issues related to disclosure of test results to patients. In this perspective article, we highlight the need for and potential challenges of AD BBM results disclosure in a primary care setting. Drawing from existing studies of AD risk disclosure, we highlight key areas of consideration to maximize patient safety and comprehension of results. Resources are suggested to aid health systems in implementing BBM testing in primary care settings. Finally, we emphasize the need for further research on the accuracy of BBMs and the practice of disclosure in primary care settings.
CITATION:
Corey J. Bolton ; Ayda Rostamzadeh ; Nathaniel Chin ; Nicole R. Fowler ; Judith Heidebrink ; Annalise Rahman-Fillipiak ; Raymond R. Romano III ; Lindsay R. Clark ; Advisory Group on Risk Evidence Education in Dementia (AGREEDementia) (2025): Disclosure of Alzheimer’s disease blood-based biomarker results in a primary care setting: Opportunities and challenges. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100310
EDITORIAL : TARGETING TAU FOR ALZHEIMERS DISEASE THROUGH OGA INHIBITION
Michael S. Rafii
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CITATION:
Michael S. Rafii (2025): Editorial: Targeting tau for Alzheimers disease through OGA inhibition. The Journal of Prevention of Alzheimer’s Disease (JPAD).
CITATION:
Michael S. Rafii (2025): Editorial: Targeting tau for Alzheimers disease through OGA inhibition. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2025.8
CORTICAL MICROSTRUCTURE IN FAMILIAL FRONTOTEMPORAL DEMENTIA ASSOCIATED WITH MAPT, GRN, AND C9ORF72 PATHOGENIC VARIANTS: LOOKING BEYOND ATROPHY
Lijuan Wang, Si Cen, Li Zhao, Junfeng Tang, Pengcheng Xu, Pusheng Quan, Wencai Ding, ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Research Consortium
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BACKGROUND: This study aimed to evaluate cortical mean diffusivity (cMD) as a sensitive biomarker for early neurodegenerative changes in familial frontotemporal lobar degeneration (FTLD) associated with C9orf72, GRN, and MAPT mutations. We compared cMD with cortical thickness (cTH) in detecting subtle microstructural alterations and examined its association with clinical severity and neurofilament light chain (NFL) concentrations.
METHODS: We analyzed data from 322 participants, including symptomatic carriers of C9orf72 (n = 85), GRN (n = 56), and MAPT (n = 58) mutations, along with 123 healthy controls. Cortical microstructure was assessed using both cTH and cMD. Clinical severity was evaluated with the CDR plus NACC FTLD scale, and plasma NFL was measured as a marker of neuroaxonal injury.
RESULTS: C9orf72 carriers exhibited the most widespread cortical thinning and increased cMD, while GRN and MAPT carriers showed more regionally restricted alterations. Across all mutation groups, cMD demonstrated higher sensitivity than cTH in detecting early changes. Furthermore, cMD values were significantly correlated with CDR plus NACC FTLD scores and NFL concentrations, underscoring its relevance to disease progression.
CONCLUSION: Cortical mean diffusivity outperforms cortical thickness in detecting early microstructural changes in familial FTLD. Its strong association with both clinical severity and neurodegeneration biomarkers highlights its potential utility for early diagnosis, disease monitoring, and individualized therapeutic strategies in FTLD.
CITATION:
Lijuan Wang ; Si Cen ; Li Zhao ; Junfeng Tang ; Pengcheng Xu ; Pusheng Quan ; Wencai Ding ; ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Research Consortium (2025): Cortical microstructure in familial frontotemporal dementia associated with MAPT, GRN, and C9orf72 pathogenic variants: Looking beyond atrophy. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100306
COMPARATIVE ANALYSIS OF THE BURDEN OF YOUNG-ONSET AND LATE-ONSET DEMENTIA IN CHINA FROM 1990 TO 2021: A STUDY BASED ON GBD 2021 DATA
Ke-qiang Lu, Ke-jia Lu, Zheng-jun Ji
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BACKGROUND: Most epidemiological studies on dementia in China have focused on the elderly population, with a lack of systematic comparisons between the burden of young-onset dementia (YOD) and late-onset dementia (LOD).
METHODS: Based on data from the Global Burden of Disease (GBD) study, this research systematically evaluated changes in the burden of YOD and LOD in China over different time periods. The analysis employed average annual percentage change (AAPC), Bayesian age-period-cohort (BAPC) modeling, decomposition analysis, risk factor attribution analysis, health inequality analysis, and frontier analysis.
RESULTS: AAPC analysis showed that the growth rate of YOD has significantly outpaced that of LOD since 2012. Forecasting results indicated that the age-standardized rates for both YOD and LOD are expected to continue rising in the future. Decomposition analysis revealed that between 1990 and 2021, the main drivers of the increasing YOD burden shifted from population growth to epidemiological changes and population aging, whereas population growth remained the dominant driver for LOD. Risk factor analysis indicated that the impact of high BMI on both YOD and LOD has become increasingly pronounced. Health inequality and frontier analyses suggested that, although disparities in YOD and LOD burden across different SDI regions were not significant, there remains substantial room for improvement in managing both conditions in China.
CONCLUSION: In recent years, YOD has exhibited a more rapid increase compared to LOD, with its driving forces gradually shifting from population-related factors to epidemiological transitions. This highlights the need to strengthen identification and intervention strategies targeting younger and middle-aged populations. Tobacco use, high fasting plasma glucose, and high BMI are key modifiable risk factors shared by both YOD and LOD, with particular attention needed on the sustained impact of high BMI. Although international disparities in health inequality are not pronounced, China still holds considerable potential for improvement in the prevention and control of both YOD and LOD. Future interventions should be more forward-looking, systematic, and tailored to specific population groups.
CITATION:
Ke-qiang Lu ; Ke-jia Lu ; Zheng-jun Ji (2025): Comparative analysis of the burden of young-onset and late-onset dementia in China from 1990 to 2021: A study based on GBD 2021 data. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100307
SYSTEMATIC REVIEW AND META-ANALYSIS OF RURAL-URBAN DISPARITIES IN ALZHEIMER’S DISEASE DEMENTIA PREVALENCE
Abe Mollalo, Mackenzie Kramer, Maxwell Cutty, Benyamin Hoseini
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BACKGROUND: The prevalence of Alzheimer’s disease (AD) dementia varies between rural and urban areas worldwide, with studies reporting mixed patterns. In this study, we conducted a systematic review and meta-analysis to pool the odds ratio (OR) of rural-to-urban prevalence and explored contributing regional and socioeconomic factors.
METHODS: We performed comprehensive searches in PubMed, MEDLINE, CINAHL, Web of Science, and Scopus (January 2000-August 2024) for peer-reviewed studies reporting individual-level AD dementia prevalence comparisons between rural and urban settings. A random-effects model was used to calculate pooled OR at a 95 % confidence interval (CI). Prespecified subgroup analyses examined variations by WHO-defined regions, healthcare expenditure, income level, and educational attainment.
RESULTS: The meta-analysis incorporated 19 studies (22 datasets, N = 584,863) and found significantly higher AD dementia prevalence in rural areas (pooled OR = 1.247, 95 % CI: 1.059–1.468), with considerable between-study heterogeneity (I2=95.5 %). Regional subgroup analyses revealed marked disparities in the Western Pacific (OR = 1.416, 95 % CI: 1.083–1.851) and Southeast Asia (OR = 1.382, 95 % CI: 1.058–1.805), contrasting with nonsignificant findings in the Americas (OR = 0.989, 95 % CI: 0.785–1.247). Socioeconomic stratification showed pronounced rural disadvantages in: (1) lower healthcare expenditure regions (≤7.5 % GDP: OR = 1.268, 95 % CI: 1.043–1.542) and (2) among lower-middle to upper-middle income countries (OR = 1.260, 95 % CI: 1.030–1.542). This disparity attenuated in high-income settings (OR = 1.206, 95 % CI: 0.979–1.486) and in regions with healthcare expenditure >7.5 % GDP (OR = 1.16, 95 % CI: 0.87–1.53). Educational stratification revealed significant rural-urban disparities in regions with lower educational attainment (≤8.1 mean schooling years: OR=1.43, 95 % CI: 1.15–1.79). In contrast, regions with higher educational attainment (>8.1 years) showed no significant difference (OR=1.05, 95 % CI: 0.89–1.25).
CONCLUSION: This review provides useful evidence that AD dementia prevalence is higher in rural areas than in urban areas, particularly in resource-limited settings. Our findings call for targeted rural interventions in vulnerable regions and further research into how healthcare infrastructure and education jointly influence AD dementia disparities.
CITATION:
Abe Mollalo ; Mackenzie Kramer ; Maxwell Cutty ; Benyamin Hoseini (2025): Systematic review and meta-analysis of rural-urban disparities in Alzheimer’s disease dementia prevalence. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100305
CHILDHOOD MALTREATMENT CONFERS LONG-TERM RISK FOR COGNITIVE IMPAIRMENT: A PROSPECTIVE INVESTIGATION
Stephanie Assuras, Kellie Courtney, Molly Maxfield, Shaina Shagalow, Sara Sherer, Jennifer J. Manly, Cathy Spatz Widom
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IMPORTANCE: Childhood maltreatment has been associated with greater risk for Alzheimer's disease and related dementias. Better understanding of this association will have implications for prevention and intervention efforts.
OBJECTIVE: To determine whether individuals with documented histories of childhood maltreatment and matched controls differ in cognitive functioning in late midlife and whether maltreatment leads to higher rates of cognitive impairment.
DESIGN: Prospective cohort design.
SETTING: Metropolitan Midwestern county area.
PARTICIPANTS: Children with documented maltreatment histories and demographically matched controls were followed up into late midlife (N = 447, Mage = 59.4). Control group children were matched to maltreated children on age, sex, race and ethnicity, and approximate family social class during the time the cases were processed.
EXPOSURE: Children with documented cases of physical and sexual abuse and neglect during 1967 to 1971 in the county juvenile (family) or adult criminal courts. Cases were restricted to children ages 0–11 at the time of the maltreatment to ensure that the temporal direction of consequences was clear.
MAIN OUTCOME AND MEASURES: Using a comprehensive neuropsychological assessment battery, multiple tests of cognitive functioning and the Functional Activities Questionnaire were administered. Participants were categorized as having cognitive impairment with no dementia (CIND) or dementia.
RESULTS: Individuals with histories of childhood maltreatment performed worse on all 12 neuropsychological tests, compared to matched controls (Cohen’s d 0.28 to 0.42) and had significantly higher risk for CIND [AOR = 1.86), amnestic CIND [AOR = 1.68) and non-amnestic [AOR = 1.48). About 13 % of maltreated individuals met criteria for amnestic CIND. Few met criteria for dementia. Males, females, Blacks, Whites, older and younger individuals, and those physically or sexually abused or neglected showed the effects of maltreatment.
CONCLUSIONS AND RELEVANCE: Cognitive repercussions of childhood maltreatment continue into late midlife. Findings reinforce the importance of early detection and preventive interventions that may decrease risks associated with childhood maltreatment in later adulthood. Because we use documented court cases from childhood, this design reduces potential biases associated with reliance on retrospective self-reports of childhood adversities. To our knowledge, this is the first study to examine long-term consequences of childhood neglect for cognitive impairment.
CITATION:
Stephanie Assuras ; Kellie Courtney ; Molly Maxfield ; Shaina Shagalow ; Sara Sherer ; Jennifer J. Manly ; Cathy Spatz Widom (2025): Childhood maltreatment confers long-term risk for cognitive impairment: A prospective investigation. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100303
ORGAN-SPECIFIC PROTEOMIC AGING AND COGNITIVE PERFORMANCE: IMPLICATIONS FOR RISK PREDICTION OF ALZHEIMER’S DISEASE AND RELATED DEMENTIAS IN OLDER ADULTS
Sujin Kang, Susan Baker, Benedict Hayhoe, Geraint Price, Gerald Novak, Janice Wong, Lefkos Middleton, Oliver Robinson
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BACKGROUND AND OBJECTIVES: Biological aging, characterized by cellular and molecular changes, may play a key role in neurodegenerative diseases. While recent proteomic advancements have introduced new aging clocks, widespread validation remains necessary. This study evaluated organ-specific and cognition-enriched proteomic clocks in relation to chronological age and cognitive change.
METHODS: We analyzed plasma proteomic data from the CHARIOT PRO SubStudy (N = 409), measured using the SomaScan assay (version 4.1) at four time points over three years (months 0, 12, 24, and 36). Using published proteomic organ age weights, we calculated conventional, organ-specific, and cognition-enriched biological ages and compared them with chronological age. Adjusted multilevel regression analyses assessed associations between baseline proteomic AgeGaps (biological−chronological age differences) and cognitive performance over 54 months.
RESULTS: The cohort (mean age: 71.8 ± 5.5 years; 50.1 % female) showed moderate to strong correlations between proteomic ages and chronological age (r = 0.37–0.80; MAE = 4.2–2.7). Over three years, AgeGaps increased across the conventional, organismal, muscle, liver, artery, and immune systems, ranging from 2.1 ± 1.9 to 1.0 ± 2.3 years. The artery AgeGap was most strongly associated with cognitive decline, with conventional and organismal AgeGaps showing similar patterns. Higher baseline AgeGap z-scores (i.e., greater biological age) in the artery and brain were associated with poorer cognition, as measured by the Repeatable Battery for the Assessment of Neuropsychological Status Total Scores (Coeff. −3.0, 95 % CI: −3.4, −2.5; and −1.1, 95 % CI: −1.5, −0.6) and the Preclinical Alzheimer's Cognitive Composite (Coeff. −0.5, 95 % CI: −0.6, −0.4; and −0.14, 95 % CI: −0.3, −0.03).
CONCLUSIONS: These findings highlight the interplay between neurological function and cardiovascular aging in cognitive decline. Organ-specific biological age assessments may aid in the early detection of age-related changes, informing personalized interventions. Our study underscores the importance of proteomic aging signatures in elucidating Alzheimer’s disease mechanisms and other neurodegenerative conditions, advocating for an integrated approach to brain and cardiovascular health.
CITATION:
Sujin Kang ; Susan Baker ; Benedict Hayhoe ; Geraint Price ; Gerald Novak ; Janice Wong ; Lefkos Middleton ; Oliver Robinson (2025): Organ-specific proteomic aging and cognitive performance: Implications for risk prediction of Alzheimer’s disease and related dementias in older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100274
RESULTS OF THE FIRST-IN-HUMAN, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE- AND MULTIPLE-ASCENDING DOSE STUDY OF BIIB113 IN HEALTHY VOLUNTEERS
Flavia C. Nery, Maciej Kaliszczak, Ben Suttle, Lori Jones, Shuang Wu, Jing Xie, Gioacchino Curiale, Esin Yesilalan, Beth Hirschhorn, Denisa Wilkes, Dave Singh, Martin Bolin, Sangram Nag, Andrea Varrone, Per Stenkrona, Anton Forsberg Morén, Christer Halldin, Jeffrey Yachnin, H. Moore Arnold, Szofia Bullain, Jaren Landen, Diana Gallagher, Heike Hering
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BACKGROUND: Preclinical studies have demonstrated that inhibition of the O-linked β-N-acetylglucosaminidase enzyme increases tau O-linked β-N-acetylglucosaminylation and may attenuate tau pathology in Alzheimer’s disease.
OBJECTIVES: To examine the safety, tolerability, pharmacokinetics, and target occupancy of single- and multiple-ascending oral doses of the small-molecule O-linked β-N-acetylglucosaminidase inhibitor, BIIB113.
DESIGN: Study 276HV101 was a first-in-human, multicenter, Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose trial.
SETTING: 72 participants were enrolled from February 2022 through July 2023.
PARTICIPANTS: Adult healthy female and infertile/vasectomized male participants.
INTERVENTION: In the single-ascending dose substudy, participants received a single dose of placebo or BIIB113 0.5, 3, 15, or 50 mg. In the 14-day multiple-ascending dose substudy, participants received placebo or BIIB113 15 or 50 mg once daily. In the target occupancy substudy, participants received either a single dose of BIIB113 0.5 or 3 mg or a once-daily dose of BIIB113 0.5 mg.
MEASUREMENTS: Safety and tolerability were measured by incidence of adverse events. Pharmacokinetic and concentration-time profiles were assessed. Target occupancy was evaluated using the carbon-11 BIO-1819,578 radioligand.
RESULTS: BIIB113 was generally well tolerated. Pharmacokinetics were linear over the dose range, with a half-life of approximately 30 h. Administration with food decreased the rate but did not affect the extent of absorption. There were no clinically meaningful differences in pharmacokinetics between elderly and nonelderly participants. Multiple once-daily doses of BIIB113 0.5 mg maintained a target occupancy of ≥90 % up to 48 h.
CONCLUSIONS: BIIB113 was well tolerated and achieved high levels of target occupancy.
CITATION:
Flavia C. Nery ; Maciej Kaliszczak ; Ben Suttle ; Lori Jones ; Shuang Wu ; Jing Xie ; Gioacchino Curiale ; Esin Yesilalan ; Beth Hirschhorn ; Denisa Wilkes ; Dave Singh ; Martin Bolin ; Sangram Nag ; Andrea Varrone ; Per Stenkrona ; Anton Forsberg Morén ; Christer Halldin ; Jeffrey Yachnin ; H. Moore Arnold ; Szofia Bullain ; Jaren Landen ; Diana Gallagher ; Heike Hering (2025): Results of the first-in-human, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study of BIIB113 in healthy volunteers. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100302
MULTIMODAL NEUROIMAGING UNVEILS BASAL FOREBRAIN-LIMBIC SYSTEM CIRCUIT DYSREGULATION IN COGNITIVE IMPAIRMENT WITH DEPRESSION: A PATHWAY TO EARLY DIAGNOSIS AND INTERVENTION
Xiaowen Xu, Xiereniguli Anayiti, Peiying Chen, Zhongfeng Xie, Mengling Tao, Yongsheng Xiang, Mingyu Tan, Yingying Liu, Ling Yue, Shifu Xiao, Peijun Wang
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BACKGROUND: Alzheimer’s disease (AD) frequently co-occurs with depressive symptoms, exacerbating both cognitive decline and clinical complexity, yet the neural substrates linking this co-occurrence remain poorly understood. We aimed to investigate the role of basal forebrain-limbic system circuit dysregulation in the interaction between cognitive impairment and depressive symptoms, identifying potential biomarkers for early diagnosis and intervention.
METHODS: This cross-sectional study included participants stratified into normal controls (NC), cognitive impairment without depression (CI-nD), and cognitive impairment with depression (CI-D). Multimodal MRI (structural, diffusion, functional, perfusion, iron-sensitive imaging) and plasma biomarkers were analyzed. Machine learning models classified subgroups using neuroimaging features.
RESULTS: CI-D exhibited distinct basal forebrain-limbic circuit alterations versus CI-nD and NC: (1) Elevated free-water fraction (FW) in basal forebrain subregions (Ch123/Ch4, p < 0.04), indicating early neuroinflammation; (2) Increased iron deposition in the anterior cingulate cortex and entorhinal cortex (p < 0.05); (3) Hyperperfusion and functional hyperactivity in Ch123 and amygdala; (4) Plasma neurofilamentlightchain exhibited correlated with hippocampal inflammation in CI-nD (p = 0.03) but linked to basal forebrain dysfunction in CI-D (p < 0.05). Multimodal support vector machine achieved 85 % accuracy (AUC=0.96) in distinguishing CI-D from CI-nD, with Ch123 and Ch4 as key discriminators. Pathway analysis in the CI-D group further revealed that FW-related neuroinflammation in the basal forebrain (Ch123/Ch4) indirectly contributed to cognitive impairment via structural atrophy.
CONCLUSION: We identified a neuroinflammatory-cholinergic pathway in the basal forebrain as an early mechanism driving depression-associated cognitive decline. Multimodal imaging revealed distinct spatiotemporal patterns of circuit dysregulation, suggesting neuroinflammation and iron deposition precede structural degeneration. These findings position the basal forebrain-limbic system circuit as a therapeutic target and provide actionable biomarkers for early intervention in AD with depressive symptoms.
CITATION:
Xiaowen Xu ; Xiereniguli Anayiti ; Peiying Chen ; Zhongfeng Xie ; Mengling Tao ; Yongsheng Xiang ; Mingyu Tan ; Yingying Liu ; Ling Yue ; Shifu Xiao ; Peijun Wang (2025): Multimodal neuroimaging unveils basal forebrain-limbic system circuit dysregulation in cognitive impairment with depression: a pathway to early diagnosis and intervention. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100298
POLYUNSATURATED FATTY ACIDS, APOE GENOTYPES, AND DEMENTIA INCIDENCE AND MORTALITY AMONG HYPERTENSIVE ADULTS
Yubo Zhang, Jindi Li, Shaohui Liu, Quanhong Chen, Xuexiu Wang, Sisi He, Yadong Wei, Yunfeng Zou, Yunan Xu, Lijun Wang, Hao Chen
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BACKGROUND: Individuals with hypertension have an elevated risk of dementia. The potential protective effects of dietary polyunsaturated fatty acids (PUFAs) against dementia remain unclear. In this study, we investigate associations between blood PUFA levels and dementia outcomes, while considering the genetic predisposition among hypertensive adults.
METHODS: We employed data from UK Biobank and a prospective cohort of 123,235 hypertensive participants aged 40–69 years were included for the analysis (2006–2022). Cox proportional hazards models adjusting for covariates were applied to assess the associations of blood levels of docosahexaenoic acid (DHA), N3FA, N6FA, linoleic acid (LA), total PUFA, and the N6FA/N3FA ratio with incident dementia, dementia mortality, and all-cause mortality. The analyses were also stratified by polygenic risk scores (PRS) or APOE genotypes.
RESULTS: Higher levels of DHA (HR 0.41, 95 % CI 0.27–0.62), N3FA, LA, N6FA, and total PUFA were associated with significantly reduced dementia incidence (P < 0.001). In contrast, a higher N6FA/N3FA ratio was linked to increased dementia risk. Similar trends were observed for mortality. APOE genotypes, rather than PRS, modified PUFA–dementia associations: individuals with low-to-moderate APOE risk showed greater protective effects of high PUFA levels compared to those with high-risk genotypes.
CONCLUSIONS: Among hypertensive adults, higher PUFA levels are associated with reduced risks of dementia and mortality. An imbalanced N6FA/N3FA ratio increases risk, while APOE genotypes significantly modify PUFA-related dementia outcomes.
CITATION:
Yubo Zhang ; Jindi Li ; Shaohui Liu ; Quanhong Chen ; Xuexiu Wang ; Sisi He ; Yadong Wei ; Yunfeng Zou ; Yunan Xu ; Lijun Wang ; Hao Chen (2025): Polyunsaturated fatty acids, APOE genotypes, and dementia incidence and mortality among hypertensive adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100297
CAN NON-PHARMACOLOGICAL INTERVENTIONS CHANGE LEVELS OF NEUROFILAMENT LIGHT IN OLDER ADULTS AT RISK OF DEMENTIA? A SECONDARY ANALYSIS OF THE SCD-WELL RANDOMIZED CLINICAL TRIAL
Lehané Masebo, Tim Whitfield, Harriet Demnitz-King, Amanda Heslegrave, Géraldine Poisnel, Antoine Lutz, Eric Frison, Miranka Wirth, Abdul Hye, Frank Jessen, Nicholas J. Ashton, Henrik Zetterberg, Natalie L. Marchant
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BACKGROUND: Older adults with subjective cognitive decline (SCD) and/or elevated neurofilament light (NfL), a neurodegeneration biomarker, are at increased risk of dementia. Non-pharmacological interventions offer a promising strategy for reducing dementia risk, yet none have utilized NfL as a marker of response in dementia prevention trials.
OBJECTIVE: To investigate the effects of two non-pharmacological interventions on NfL in older adults with SCD.
DESIGN: SCD-Well was an 8-week observer-blinded, randomized, clinical trial with 6-month follow-up, and was a part of the Horizon 2020 European Union-funded "Medit-Ageing" project. Data were analyzed from June 2022 to August 2024.
SETTING: Memory clinics at four sites in France, Germany, Spain, and UK.
PARTICIPANTS: Participants were enrolled from March 2017 to January 2018 after fulfilling SCD research criteria and performing within the normal range on cognitive testing. Of the 147 participants enrolled, 140 were included in this secondary analysis (7 did not consent to venipuncture).
INTERVENTIONS: Participants were randomly allocated to the Caring Mindfulness-Based Approach for Seniors (CMBAS) intervention or a structurally matched Health Self-Management Program (HSMP).
MEASUREMENTS: Plasma NfL was measured at baseline (V1), post-intervention (V2), and 6-month follow-up (V3), using Single molecule array technology, and log-transformed for analyses.
RESULTS: 137 older adults with SCD provided NfL data (mean [SD] age: 72.7 [6.8] years; 62.0 % female; CMBAS, n = 70; HSMP, n = 67). NfL data were available at V1 (n = 136), V2 (n = 119) and V3 (n = 115). The visit-by-arm interaction was not statistically significant, and no significant changes in NfL were observed within the CMBAS or HSMP arms from V1 to V2. However, within the HSMP arm, NfL levels reduced from V1 to V3 (-0.10, 95 % confidence interval [-0.18 to -0.02]). Modified intention-to-treat analyses, which included 140 participants, supported these findings, and additionally recorded significant reductions in the HSMP arm from V1 to V2 (n = 140, -0.07 [-0.14 to -0.00]).
CONCLUSIONS: In this study, NfL levels were reduced at 6-month follow-up after a health self-management program. Future interventions with longer duration, extended follow-up and clinical endpoints will help clarify whether NfL reductions are sustained over extended timeframes and translate to lower dementia incidence.
CITATION:
Lehané Masebo ; Tim Whitfield ; Harriet Demnitz-King ; Amanda Heslegrave ; Géraldine Poisnel ; Antoine Lutz ; Eric Frison ; Miranka Wirth ; Abdul Hye ; Frank Jessen ; Nicholas J. Ashton ; Henrik Zetterberg ; Natalie L. Marchant (2025): Can non-pharmacological interventions change levels of neurofilament light in older adults at risk of dementia? A secondary analysis of the SCD-Well randomized clinical trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100299
TRAJECTORIES OF MUSCLE STRENGTH AND PHYSICAL PERFORMANCE PRECEDING DEMENTIA IN OLDER US AND EUROPEAN POPULATIONS
Youjin Jiang, Yi Ding, Qiuyu Cao, Xianglin Wu, Xiaoran Li, Yu Xu, Zhiyun Zhao, Min Xu, Jieli Lu, Tiange Wang, Guang Ning, Weiqing Wang, Yufang Bi, Yuchen Xu, Mian Li
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BACKGROUND: The association between muscle function and dementia risk remains elusive, as studies suggest that impaired muscle function may act as both a risk factor for and a consequence of dementia, hindering causal inference.
OBJECTIVES: We aimed to clarify the temporal relationship between muscle function and incident dementia by investigating non-linear trajectories of muscle function in the years preceding dementia onset in older US and European populations.
DESIGN: Case-control study.
SETTING: Data were combined from the English Longitudinal Study of Ageing (ELSA, 2004–2018, waves 2–9), Health and Retirement Study (HRS, 2004–2018, waves 7–14), and Survey of Health, Ageing and Retirement in Europe (SHARE, 2004–2017, waves 1–7).
PARTICIPANTS: For handgrip strength analysis, 18,335 participants aged 60 and older were included from the ELSA, HRS, and SHARE cohorts. For gait speed analysis, 11,690 participants aged 60 and older were included from the ELSA and HRS cohorts.
MEASUREMENTS: Muscle strength was assessed by handgrip strength using a Smedley dynamometer, and physical performance was evaluated by gait speed using the Timed 8-Foot Walk test, with assessments conducted biennially or quadrennially. Dementia was diagnosed using self-reported physician diagnosis and cognitive-functional assessments. Trajectories of muscle strength and physical performance were analyzed on a backward timescale using latent-process mixed models within a nested case-control design.
RESULTS: Significant differences in muscle function trajectories were observed between cases and controls 12 and 13 years prior to dementia onset (handgrip strength: coefficient [SE], -0.23 [0.05], P < 0.001; gait speed: coefficient [SE], -0.24 [0.08], P = 0.003). The pathological trajectories of handgrip strength and gait speed revealed periods of acceleration beginning 6 and 8 years prior to diagnosis, respectively. After adjusting for pre-dementia acceleration, greater handgrip (per 1-kg increment) was associated with a modest reduction in dementia risk (hazard ratio, 0.98; 95 % CI, 0.97–0.99), while faster gait speed (per 1-m/s increment) markedly lowered risk (hazard ratio, 0.35; 95 % CI, 0.23–0.53).
CONCLUSIONS: These findings highlight muscle function as a cost-effective tool for early detection and dynamic monitoring of dementia risk and identify it as a modifiable target for prevention. Muscle function may also assist in identifying high-risk groups for preferential enrollment into clinical trials for dementia prevention and treatment.
CITATION:
Youjin Jiang ; Yi Ding ; Qiuyu Cao ; Xianglin Wu ; Xiaoran Li ; Yu Xu ; Zhiyun Zhao ; Min Xu ; Jieli Lu ; Tiange Wang ; Guang Ning ; Weiqing Wang ; Yufang Bi ; Yuchen Xu ; Mian Li (2025): Trajectories of muscle strength and physical performance preceding dementia in older US and European populations. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100296
UNDERDETECTION OF NEUROCOGNITIVE DISORDERS IN SOUTHERN ITALY: EVIDENCE FROM THE SALENTO REGION
Davide Vilella, Daniele Urso, Agnese Valguarnera, Giuseppe Volpe, Valentina Gnoni, Eleonora Rollo, Alessia Giugno, Marcella Caggiula, Brigida Coluccia, Annamaria Mauro, Roberta Barone, Miriam Accogli, Marzia Leopizzi, Alessandro Introna, Marco Musio, Stefano Giannoni-Luza, Giancarlo Logroscino
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BACKGROUND: Neurocognitive disorders, including dementia and mild cognitive impairment, are increasingly prevalent, demanding efficient detection and management strategies.
OBJECTIVES: This study is part of the Puglia Region’s initiative under the Italian Dementia National Plan (DNP) and aimed to assess the capacity of the Lecce province healthcare system to identify new neurocognitive disorders cases by comparing observed cases with expected rates derived from meta-analyses and Global Burden of Disease estimates.
DESIGN: Using complete case ascertainment across 10 hospital-based and community centers, a total of 857 incident cases were identified in one year, including 441 Minor neurocognitive disorders (51.46 %) and 416 major neurocognitive disorders cases (48.54 %).
SETTING: Public Centers for Cognitive Disorders and Dementia (CCDDs) across hospital and community services in the Lecce province, Southern Italy.
PARTICIPANTS: Eligible participants included all individuals aged between 65 and 89 residing in the Lecce province who received a diagnosis of neurocognitive disorder. 857 participants were enrolled (519 females – 338 males).
MEASUREMENTS: Incident cases of neurocognitive disorder, both minor and major, accordingly to DSM-5 criteria.
RESULTS: Only 10.65 % of expected major neurocognitive disorders and 7.24 % of expected minor neurocognitive disorders cases were detected, with significant age and sex disparities, with higher underdetection rates in females. Detection rates declined with advancing age, with the observed-to-expected ratio for major neurocognitive disorders falling from 18.23 % in individuals aged 65–69 years to just 5.24 % in those aged 85–89 years. These findings were validated against Global Burden of Disease estimates.
CONCLUSIONS: This study highlights the critical gaps in detecting neurocognitive disorders, particularly in older adults and prodromal stages such as minor neurocognitive disorders, where early intervention could yield the greatest benefits. The findings underscore the urgent need for targeted reforms to improve e diagnostic pathways and better align healthcare systems with emerging disease-modifying therapies and preventive strategies.
CITATION:
Davide Vilella ; Daniele Urso ; Agnese Valguarnera ; Giuseppe Volpe ; Valentina Gnoni ; Eleonora Rollo ; Alessia Giugno ; Marcella Caggiula ; Brigida Coluccia ; Annamaria Mauro ; Roberta Barone ; Miriam Accogli ; Marzia Leopizzi ; Alessandro Introna ; Marco Musio ; Stefano Giannoni-Luza ; Giancarlo Logroscino (2025): Underdetection of neurocognitive disorders in Southern Italy: Evidence from the Salento region. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100295
LETTER TO THE EDITOR : THE SINGAPORE DEMENTIA PREVENTION PROGRAMME: TEN YEARS ON AND LOOKING AHEAD
Lei Feng, Kaisy Xinhong Ye, Lee Gan Goh, Ee-Heok Kua
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CITATION:
Lei Feng ; Kaisy Xinhong Ye ; Lee Gan Goh ; Ee-Heok Kua (2025): Letter to the Editor : The singapore demen-tia prevention programme: Ten years on and looking ahead. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100272
ASSOCIATIONS OF CARDIOVASCULAR HEALTH ASSESSED BY LIFE’S CRUCIAL 9 WITH INCIDENT CARDIOVASCULAR DISEASE AND DEMENTIA: A PROSPECTIVE COHORT STUDY
Yiwen Dai, Yuling Liu, Yang Pan, Jingya Ma, Jie Liang, Wenya Zhang, Xuyang Diao, Menghan Zhu, Xinqing Yang, Darui Gao, Yanyu Zhang, Mengmeng Ji, Yichi Zhang, Wuxiang Xie, Fanfan Zheng
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BACKGROUND: The associations of the renewed cardiovascular health (CVH) assessed by Life’s Crucial 9 (LC9), which consisted of Life’s Essential 8 (LE8) and psychological health, with incident cardiovascular disease (CVD) and dementia remained unexplored.
OBJECTIVES: This study aims to investigate the associations and determine whether LC9 has a higher discrimination ability than LE8 in predicting incident CVD and dementia.
DESIGN, SETTING, AND PARTICIPANTS: This study was a prospective population-based cohort study using data from the UK Biobank.
MEASUREMENTS: LC9 was assessed as American Heart Association recommended. Incident CVD and dementia were based on self-reported data, hospital inpatient records, and death register records.
RESULTS: Of 289,649 included participants, 137,480 (47.5 %) were male, and the mean age was 56.6 ± 8.1 years. Compared with participants having low LC9, those having moderate or high LC9 had lower risks of incident CVD (moderate: 0.46 [0.43–0.48]; high: 0.25 [0.23–0.27]; p for trend <0.001) and dementia (moderate: 0.57 [0.50–0.64]; high: 0.45 [0.39–0.52]; p for trend <0.001) after multivariate adjustment. Both the LE8 and LC9 achieved good discriminative performance for incident CVD (LE8 Harrell C-statistic= 0.7138 vs. LC9 Harrell C-statistic=0.7144, p = 0.136); the net reclassification improvement was estimated at 0.07 % (p = 0.749), and integrated discrimination improvement was estimated at 0.009 (p < 0.001). The results for dementia showed similar patterns.
CONCLUSIONS AND RELEVANCE: Optimal LC9 was associated with lower risks of incident CVD and dementia. Although psychological health is essential for preventing CVD and dementia, including it into CVH's evaluation criteria did not significantly improve CVH's predictive performance.
CITATION:
Yiwen Dai ; Yuling Liu ; Yang Pan ; Jingya Ma ; Jie Liang ; Wenya Zhang ; Xuyang Diao ; Menghan Zhu ; Xinqing Yang ; Darui Gao ; Yanyu Zhang ; Mengmeng Ji ; Yichi Zhang ; Wuxiang Xie ; Fanfan Zheng (2025): Associations of cardiovascular health assessed by life’s crucial 9 with incident cardiovascular disease and dementia: A prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100273
A MULTIMODAL LIFESTYLE INTERVENTION COMPLEMENTED WITH EPIGALLOCATECHIN GALLATE TO PREVENT COGNITIVE DECLINE IN APOE- Ɛ4 CARRIERS WITH SUBJECTIVE COGNITIVE DECLINE: A RANDOMIZED, DOUBLE-BLINDED CLINICAL TRIAL (PENSA STUDY)
Laura Forcano, Natalia Soldevila-Domenech, Anna Boronat, Gonzalo Sánchez-Benavides, Albert Puig-Pijoan, Thais Lorenzo, Ana Aldea-Perona, Marc Suárez-Calvet, Aida Cuenca-Royo, Juan Domingo Gispert, Maria Gomis-Gonzalez, Carolina Minguillón, Patrícia Diaz-Pellicer, Karine Fauria, Iris Piera, Klaus Langohr, Mara Dierssen, Nieves Pizarro, Esther Mur-Gimeno, Oriol Grau-Rivera, José Luis Molinuevo, Rafael de la Torre, the PENSA working group
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BACKGROUND: The potential of dietary compounds to enhance the effects of multimodal lifestyle interventions (MLIs) on cognition in individuals at high risk of cognitive impairment remains unclear.
OBJECTIVES: To assess whether the addition of a green tea extract enriched with epigallocatechin-3-gallate (EGCG) enhances the effects of an MLI.
DESIGN: Double-blind, randomized, two-arm, and placebo-controlled trial. Exploratory comparisons were made with a non-randomized group (NRG) receiving healthy lifestyle recommendations. Setting: Population-based study conducted in Barcelona, Spain
PARTICIPANTS: APOE-ɛ4 carriers aged 60-80 with subjective cognitive decline.
INTERVENTION: A 12-month intensive MLI including dietary counseling, guided physical activity, and cognitive stimulation, combined with EGCG (5-6 mg/kg) or placebo, followed by a 3-month washout.
MEASUREMENTS: Primary endpoint was change in the modified Preclinical Alzheimer Cognitive Composite (PACC-exe) score.
RESULTS: 129 participants (65.1% 84 women, aged 66.7±5.5 years) were enrolled (52 MLI+EGCG, 52 MLI+placebo and 25 NRG), with126 (97.7%) included in the modified intention-to-treat analysis. After 12 months, no statistically significant difference was observed between MLI+EGCG and MLI+placebo in the PACC-exe (adjusted mean difference [AMD]: 0.12; 95%CI: -0.01, 0.24; p=0.061). However, participants in the MLI+EGCG group were 2.6 times more likely to show a reliable cognitive improvement. In exploratory analyses following a 3-month washout, the MLI+EGCG group showed significant cognitive benefits compared to the MLI+placebo (AMD: 0.19; 95%CI: 0.06, 0.32; p=0.005). Exploratory comparisons with the NRG also suggested greater gains in cognition and dementia risk reduction in both MLI groups, particularly with EGCG.
CONCLUSIONS: While the primary outcome was not met, this proof-of-concept trial suggests that combining MLIs with EGCG warrants further investigation in larger, confirmatory studies.
CITATION:
Laura Forcano ; Natalia Soldevila-Domenech ; Anna Boronat ; Gonzalo Sánchez-Benavides ; Albert Puig-Pijoan ; Thais Lorenzo ; Ana Aldea-Perona ; Marc Suárez-Calvet ; Aida Cuenca-Royo ; Juan Domingo Gispert ; Maria Gomis-Gonzalez ; Carolina Minguillón ; Patrícia Diaz-Pellicer ; Karine Fauria ; Iris Piera ; Klaus Langohr ; Mara Dierssen ; Nieves Pizarro ; Esther Mur-Gimeno ; Oriol Grau-Rivera ; José Luis Molinuevo ; Rafael de la Torre ; the PENSA working group (2025): A multimodal lifestyle intervention complemented with epigallocatechin gallate to prevent cognitive decline in APOE- ɛ4 carriers with Subjective Cognitive Decline: a randomized, double-blinded clinical trial (PENSA study). The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100271
STRESS INTERNALIZATION IS A TOP RISK FOR AGE-ASSOCIATED COGNITIVE DECLINE AMONG OLDER CHINESE IN THE U.S
Michelle H Chen, Yiming Ma, Charu Verma, Stephanie Bergren, William T Hu
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BACKGROUND: Behavioral and sociocultural factors are often examined in population-based studies as independent variables, yet latent factors often influence multiple behaviors all at once. This may be especially true in immigrant populations living in or near ethnic enclaves. Better characterization of internal or external factors underlying multiple behaviors is critical to modify the root causes of health-related behaviors.
OBJECTIVES: To identify inter-relatedness of multiple internal (acculturation, behavior, well-being) and external (neighborhood & community) characteristics, as well as their influence on age-associated cognitive decline in a large group of non-demented older Chinese Americans living in the Chicago metropolitan area.
SETTING: Secondary data analysis of the Population Study of ChINese Elderly (PINE).
PARTICIPANTS: 1528 non-demented older Chinese Americans (aged 60+) who attended three waves of PINE.
DESIGN: Longitudinal cohort study.
INTERVENTION(S): Not applicable.
MEASUREMENTS: Three psychobehavioral and 3 sociocultural factors were included in factor analysis for independent variables; Chinese versions of the Mini-Mental State Examination, East Boston Memory Test, Digit Span Backward, and oral Symbol Digit Modalities Test were included in principal component analysis to derive dependent variables.
RESULTS: Factor analysis identified three main behavioral/sociocultural constructs: stress internalization, neighborhood/community cohesion, and external stress alleviation. Among these, only stress internalization – consisting of greater perceived stress, greater hopelessness, and lower conscientiousness – was associated with longitudinal decline in memory, while none with decline in executive functioning. Neither acculturation nor activity engagement was related to longitudinal decline in memory or executive functioning, even though participants with greater acculturation or activity engagement had better baseline cognitive performance.
CONCLUSIONS: Only the factor underlying stress processing, hopelessness, and conscientiousness was associated with rates of longitudinal memory decline in this older non-demented Chinese American cohort. These maladaptive traits have been linked to the Asian model minority stereotype but all the same potentially modifiable. Limitations include potential selection bias, potential cultural inappropriateness of the measures, and limited cognitive test battery and clinical information.
CITATION:
Michelle H Chen ; Yiming Ma ; Charu Verma ; Stephanie Bergren ; William T Hu (2025): Stress internalization is a top risk for age-associated cognitive decline among older Chinese in the U.S. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100270
CTAD TASKFORCE: GENETIC THERAPIES IN ALZHEIMER’S DISEASE
D. Jakabek, A.M. Isaacs, B. De Strooper, M. Tuszynski, R. Lane, O. Uspenskaya, E. McDade, M.S. Rafii, C.J. Mummery
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There are an increasing number of genetic approaches to treating Alzheimer’s disease and other dementias, with some promising results from early-phase trials. This prompted the convention of the first EU-US CTAD Task Force on genetic therapies in Alzheimer’s disease in October 2024. Preclinical studies and clinical trials of genetic therapies in Alzheimer’s disease and other dementias are presented here with key lessons for the field. Importantly, there are several challenges and opportunities unique to neurogenetic therapies which were reviewed and discussed, including means of genetic manipulation, adverse events, monitoring, timing of therapy, and the importance of patient involvement in trial design. Continued collaboration across disciplines will accelerate development of neurogenetic therapeutics.
CITATION:
D. Jakabek ; A.M. Isaacs ; B. De Strooper ; M. Tuszynski ; R. Lane ; O. Uspenskaya ; E. McDade ; M.S. Rafii ; C.J. Mummery (2025): CTAD taskforce: genetic therapies in Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100269
SYNERGISTIC EFFECTS OF MULTIPLE PATHOLOGICAL PROCESSES ON ALZHEIMER\'S DISEASE RISK: EVIDENCE FOR AGE-DEPENDENT STROKE INTERACTIONS
Fen Liu, Xuesong Xia, Chengjie Zheng, Feng Liu, Min Jiang
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BACKGROUND: Alzheimer's disease (AD) pathogenesis involves complex interactions between multiple neuropathological processes, yet traditional approaches focus on individual markers. The cumulative effects of multiple pathologies and their interactions with cerebrovascular compromise and age remain poorly understood. This study aimed to develop a comprehensive Pathological Burden Score (PBS) and examine its relationship with AD risk, including interactions with stroke history and age.
METHODS: We analyzed 11,308 participants from the National Alzheimer's Coordinating Center database. A PBS was constructed integrating six neuropathological domains: Braak neurofibrillary tangle staging, CERAD neuritic plaque density, Thal amyloid-β phasing, stroke history, white matter rarefaction severity, and cerebral atrophy severity (range 0–16 points). PBS was categorized into four burden levels: low (0–4), moderate (5–8), high (9–12), and very high (13–16). Multivariable logistic regression examined associations between PBS categories and AD risk, with formal interaction testing for stroke × PBS effects. Age-stratified analyses were conducted using a 75-year cutpoint.
RESULTS: A clear dose-response relationship was observed between PBS and AD risk, with very high burden conferring over 5-fold increased odds compared to low burden. Significant stroke × PBS interaction was detected (interaction OR 1.23, p < 0.001), with stroke amplifying pathological burden effects. Among participants with very high burden, AD risk was 92.5 % in stroke patients versus 24.1 % in non-stroke patients. Age-dependent effects were profound: younger participants (<75 years) with high burden plus stroke showed 18.67-fold increased odds, while older participants (≥75 years) with equivalent burden showed 7.89-fold increased odds.
CONCLUSIONS: Cumulative pathological burden demonstrates a strong dose-response relationship with AD risk, significantly amplified by stroke history. The pronounced age-dependent effects highlight the need for age-specific prevention strategies, with particular emphasis on aggressive vascular risk management in younger populations. These findings support comprehensive pathological burden assessment for enhanced risk stratification and personalized dementia care approaches.
CITATION:
Fen Liu ; Xuesong Xia ; Chengjie Zheng ; Feng Liu ; Min Jiang (2025): Synergistic effects of multiple pathological processes on Alzheimer's disease risk: Evidence for age-dependent stroke interactions. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100268
THE DIFFERENTIAL EFFECT OF STRENGTH, COGNITIVE AND AEROBIC TRAINING COMBINATIONS ON COGNITIVE PERFORMANCE AND FUNCTIONAL ABILITIES IN ELDERLY WITH COGNITIVE DECLINE: THE FIT4ALZ PROJECT
Ana Filipa Silva, Gilmara Assis, Rui Miguel Silva, Eugenia Murawska-Cia?owicz, Grzegorz Zurek, José Carvalho, Mafalda Sofia Roriz, José Alberto Azevedo, António Sampaio, Telmo Bento, Olivera Jovanovic, Marko Adamovic, Spartaco Grieco, Roberta Germini, Filipe Manuel Clemente
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BACKGROUND: Despite the global impact of neurodegenerative diseases and ongoing research efforts, pharmacological therapies have shown limited benefits. In contrast, physical exercise, with no side effects, has emerged as a non-pharmacological alternative that can enhance brain structure and function, promoting a healthier neurological phenotype.
OBJECTIVES: This study aimed to explore the effects of aerobic and strength training methods, both with and without cognitive training, on mitigating or reversing cognitive decline in older adults.
DESIGN, SETTING, PARTICIPANTS: In a randomized controlled trial, a total of 350 participants (average age 72.9 ± 6.0 years, 79 % female), with signs of decline (MoCA score below 26), were assigned to one of five groups: i) strength plus cognitive training (STCT, n = 92); ii) strength training (ST, n = 41); iii) aerobic training (AT, n = 97); iv) aerobic plus cognitive training (ATCT, n = 91); v) control (CG, n = 29).
INERVENTION: For 12 weeks, all groups followed a 60 min training session three times a week, tailored to their specific group, with half of the sample adding 20 min of cognitive stimulation after the physical exercise.
MEASUREMENTS: Cognitive and physical assessments were conducted at the start and end of the intervention using the MoCA and the Senior Fitness test. A mixed ANCOVA analysis revealed significant interactions between time and group for all tests.
RESULTS: After the intervention, the CG showed significantly lower scores compared to all experimental groups. The CG also performed significantly worse than the ATCT group (p < 0.001). Additionally, the ATCT outperformed the STCT in the 6-min walk test (p < 0.05), while the STCT showed superior performance in the flexibility tests (sit and reach, back scratch) compared to the CG (p < 0.05).
CONCLUSIONS: Results showed that 12-weeks of aerobic and strength training, with or without cognitive components, improved cognitive performance in older adults with cognitive decline, highlighting the importance of maintaining functional abilities for preserving skills, autonomy, independence, and quality of life in aging.
CITATION:
Ana Filipa Silva ; Gilmara Assis ; Rui Miguel Silva ; Eugenia Murawska-Ciałowicz ; Grzegorz Zurek ; José Carvalho ; Mafalda Sofia Roriz ; José Alberto Azevedo ; António Sampaio ; Telmo Bento ; Olivera Jovanovic ; Marko Adamovic ; Spartaco Grieco ; Roberta Germini ; Filipe Manuel Clemente ; (2025): The differential effect of strength, cognitive and aerobic training combinations on cognitive performance and functional abilities in elderly with cognitive decline: The Fit4Alz project. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100267
THE EFFECT OF MODIFIED DONANEMAB TITRATION ON AMYLOID-RELATED IMAGING ABNORMALITIES WITH EDEMA/EFFUSIONS AND AMYLOID REDUCTION: 18-MONTH RESULTS FROM TRAILBLAZER-ALZ 6
Hong Wang, Emel Serap Monkul Nery, Paul Ardayfio, Rashna Khanna, Diana Otero Svaldi, Sergey Shcherbinin, Wen Xu, Scott W. Andersen, Paula M. Hauck, Dawn A. Brooks, Emily C. Collins, Stephen Salloway, Mark A. Mintun, John R. Sims
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The TRAILBLAZER-ALZ 6 study (NCT05738486) evaluated the effect of different donanemab dosing regimens on amyloid-related imaging abnormalities with edema/sulcal effusions (ARIA-E). The modified titration arm met the primary outcome and significantly reduced ARIA-E frequency compared with the standard dosing while maintaining a similar pharmacodynamic effect on amyloid reduction at 24 weeks. Primary outcome and 52-week data were previously published. Completed study results at 76 weeks are reported here. ARIA-E frequencies were 15.6 % and 24.2 % in the modified titration and standard arms, respectively. ARIA-E radiographic severity was significantly lower (p = 0.015) with modified titration than with standard dosing. Additionally, symptomatic ARIA-E frequency was lower with modified titration versus standard dosing (2.8 % vs 4.8 %). The frequency of serious adverse events was comparable between the modified titration and standard dosing arms. A more gradual titration of donanemab dosing significantly reduced ARIA-E risk versus standard dosing.
CITATION:
Hong Wang ; Emel Serap Monkul Nery ; Paul Ardayfio ; Rashna Khanna ; Diana Otero Svaldi ; Sergey Shcherbinin ; Wen Xu ; Scott W. Andersen ; Paula M. Hauck ; Dawn A. Brooks ; Emily C. Collins ; Stephen Salloway ; Mark A. Mintun ; John R. Sims (2025): The effect of modified donanemab titration on amyloid-related imaging abnormalities with edema/effusions and amyloid reduction: 18-month results from TRAILBLAZER-ALZ 6. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100266
ASSOCIATION OF VITAMIN B12 DEFICIENCY IN A DEMENTIA COHORT WITH HIPPOCAMPAL ATROPHY ON MRI
Asako Ueno, Tadanori Hamano, Miwako Nagata, Tomohisa Yamaguchi, Yoshinori Endo, Soichi Enomoto, Hirohiko Kimura, Masamichi Ikawa, Osamu Yamamura, Daiki Yamanaka, Yohei Kimura, Yasunari Nakamoto, Yasuhiro Nishiyama
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BACKGROUND: Vitamin deficiencies have been reported to cause brain atrophy. Hippocampal atrophy has been well reported in patients with dementia including Alzheimer’s disease.
OBJECTIVES: To investigate the association between hippocampal atrophy and vitamin deficiency
DESIGN: Cross sectional study.
SETTING: Three sites in one country.
PARTICIPANTS: Overall, 567 patients who visited an outpatient dementia clinic and underwent MRI-VSRAD (Voxel-Based Specific RegionalAnalysis System for Alzheimer's Disease) were included in this study.
INTERVENTION: Patients with a hippocampal atrophy Z-score of < 2 were classified as normal (n = 323), and those with a Z-score of ≥ 2 were diagnosed with hippocampal atrophy (n = 244).
MEASUREMENTS: Vitamin B12, folic acid, vitamin B1, homocysteine, HbA1c, and creatinine levels were measured and their association with hippocampal atrophy was assessed. Age, MMSE (Mini Mental State Examination), and hippocampal atrophy were also evaluated.
RESULTS: In the hippocampal atrophy group, the frequency of vitamin B12 deficiency was higher (p < 0.022), MMSE score was lower (p < 0.0001), and age was higher (p < 0.0001) than that in the normal group (Mann-Whitney U test). Patients with vitamin B12 deficiency (odds ratio, 3.46) and low MMSE score (odds ratio, 2.24) had an increased risk of hippocampal atrophy.
CONCLUSION: Vitamin B12 deficiency was associated with hippocampal atrophy detected by VSRAD analysis. Therefore, early vitamin B12 supplementation should be considered in patients with deficiencies to reduce dementia risk.
CITATION:
Asako Ueno ; Tadanori Hamano ; Miwako Nagata ; Tomohisa Yamaguchi ; Yoshinori Endo ; Soichi Enomoto ; Hirohiko Kimura ; Masamichi Ikawa ; Osamu Yamamura ; Daiki Yamanaka ; Yohei Kimura ; Yasunari Nakamoto ; Yasuhiro Nishiyama (2025): Association of vitamin B12 deficiency in a dementia cohort with hippocampal atrophy on MRI. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100265
A MODELLING APPROACH TO DERIVE POPULATION-SPECIFIC CUTOFF FOR PLASMA P-TAU217
Tau Ming Liew, Alzheimer\'s Disease Neuroimaging Initiative
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Plasma pTau-217 shows promise for detecting Alzheimer’s disease, but needs population-specific cutoffs for effective use. Conventional cutoff determination relies on invasive or costly gold-standards, limiting scalability. This study evaluated Finite Mixture Modelling (FMM) for establishing cutoffs without gold-standards. FMM was applied to derive cutoffs for Lumipulse plasma p-Tau217 and p-Tau217/Aβ42 ratio among 1039 ADNI participants, with validation conducted in a subset with amyloid PET data (n = 711). Additionally, simulations were conducted to determine the minimum sample size for reliable FMM estimation. The results showed that FMM-derived cutoffs effectively classified participants into brain amyloid-negative, -positive, and -indeterminate groups, with an indeterminate proportion <20 %, negative and positive predictive values near or above 90 %, and with p-Tau217/Aβ42 outperforming p-Tau217. These FMM-derived cutoffs demonstrated test performance that surpassed several previously-established cutoffs, including the recent FDA-approved cutoff. At least 900 samples were needed for reliable cutoff estimation. In conclusion, this study demonstrated the effectiveness of a modelling approach for estimating plasma p-Tau217 cutoffs without reliance on gold-standards. This approach simplifies the determinating of population-specific cutoffs and facilitates adoption of plasma p-Tau217 in communities lacking access to gold-standards, including some LMICs.
CITATION:
Tau Ming Liew ; Alzheimer's Disease Neuroimaging Initiative (2025): A modelling approach to derive population-specific cutoff for plasma p-Tau217. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100264
THE ALZHEIMER’S DISEASE COOPERATIVE STUDY – ACTIVITIES OF DAILY LIVING DEPENDENCE SCORE: REVISION AND VALIDATION OF AN ALGORITHM EVALUATING PATIENT DEPENDENCE ACROSS THE SPECTRUM OF AD SEVERITY
Julie M. Chandler, Claire J. Lansdall, Wenyu Ye, Fiona McDougall, Mark Belger, Balazs Toth, Xiaojuan Mi, Kaycee M. Sink, Alexandra S. Atkins
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BACKGROUND: Increasing dependence on informal and formal caregivers in Alzheimer’s disease (AD) contributes to high societal cost. Treatments that delay time to increased dependence/care needs would be clinically meaningful, but these outcomes are rarely collected in early AD clinical trials. The 2015 ADCS-ADL dependence algorithm was created to estimate level of dependence in AD.
OBJECTIVES: To revise the original dependence algorithm to improve accuracy of dependence scores (DS) across AD severity, including early symptomatic AD.
DESIGN: Secondary data analysis.
SETTING: Community cohort; randomized clinical trial.
PARTICIPANTS: 14,000 participants enrolled across GERAS-EU observational study and 12 AD clinical trials.
MEASUREMENTS: Three-phase algorithm revision: 1) reassess ADCS-ADL items to identify those appropriate for assessing dependence; 2) (a) assign individual item responses to degrees of assistance and (b) to operationalize assignment of DS based on extent of total assistance needed; and 3) validate revised algorithm in multiple datasets across AD severity from mild cognitive impairment due to AD to moderate-severe AD.
RESULTS: The revised DS (0-6) algorithm classified most participants with early symptomatic AD as independent or moderately independent (DS<3) at baseline. With disease progression over time, the proportion of participants who were mildly to fully dependent (DS≥3) increased across AD severity. Increased DS was associated with incremental worsening of clinical outcomes.
CONCLUSIONS: The revised ADCS-ADL DS algorithm provides a supplementary approach to evaluate the impact of emerging treatments on independence/care needs in AD and may be useful in clinical trials where the ADCS-ADL has been collected.
CITATION:
Julie M. Chandler ; Claire J. Lansdall ; Wenyu Ye ; Fiona McDougall ; Mark Belger ; Balazs Toth ; Xiaojuan Mi ; Kaycee M. Sink ; Alexandra S. Atkins (2025): The Alzheimer’s Disease Cooperative Study – Activities of Daily Living dependence score: revision and validation of an algorithm evaluating patient dependence across the spectrum of AD severity. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100261
LETTER TO THE EDITOR: COMMENT BY EUROPEAN ALZHEIMER’S DISEASE CONSORTIUM (EADC) INVESTIGATORS ON THE NEGATIVE RECOMMENDATION OF THE CHMP ON THE MARKETING AUTHORIZATION OF DONANEMAB FOR EARLY ALZHEIMER’ S DISEASE
Frank Jessen, Javier Arbizu, Mercé Boada, Karim Bennys, Marina Boban, Katharina Bürger, Andrea Chincarini, Annachiara Cagnin, Peter Paul De Deyn, Emrah Düzel, Sebastiaan Engelborghs, Michael Ewers, Lieza G. Exalto, Wiesje M. van der Flier, Juan Fortea, Kristian Steen Frederiksen, Giovanni B Frisoni, Lutz Frölich, Alejandro J. Garza-Martinez, Timo Grimmer, Bernard Hanseeuw, Jakub Hort, Adrian Ivanoiu, Patrick G Kehoe, Sean P Kennelly, Silke Kern, Stefan Klöppel, Lenka Kraj?ovi?ová, Milica G. Kramberger, Bernadette McGuinness, Patrizia Mecocci, Timo Jan Oberstein, Pierre-Jean Ousset, Claire Paquet, Robert Perneczky, Fabrizio Piazza, Domenico Plantone, Innocenzo Rainero, Guillaume Sacco, Eric Salmon, Isabel Santana, Nikolaos Scarmeas, Anja Schneider, Jonathan M Schott, Eino Solje, Elka Stefanova, Elisabeth Stögmann, Mélanie Strauss, Stanislav Sutovsky, Gunhild Waldemar, Bengt Winblad
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CITATION:
Frank Jessen ; Javier Arbizu ; Mercé Boada ; Mircea Balasa ; Karim Bennys ; Marina Boban ; Katharina Bürger ; Andrea Chincarini ; Annachiara Cagnin ; Peter Paul De Deyn ; Emrah Düzel ; Sebastiaan Engelborghs ; Michael Ewers ; Lieza G. Exalto ; Wiesje M. van der Flier ; Juan Fortea ; Kristian Steen Frederiksen ; Giovanni B Frisoni ab, Lutz Frölich ; Alejandro J. Garza-Martinez ; Timo Grimmer ; Bernard Hanseeuw ; Jakub Hort ag, Adrian Ivanoiu ; Patrick G Kehoe ; Sean P Kennelly ; Silke Kern ; Stefan Klöppel ; Lenka Krajčovičová ; Milica G. Kramberger ; Bernadette McGuinness ; Patrizia Mecocci ; Timo Jan Oberstein ; Pierre-Jean Ousset ; Claire Paquet ; Robert Perneczky ; Fabrizio Piazza ; Domenico Plantone ; Innocenzo Rainero ; Guillaume Sacco ; Eric Salmon ; Isabel Santana ; Nikolaos Scarmeas ; Anja Schneider ; Jonathan M Schott ; Eino Solje ; Elka Stefanova ; Elisabeth Stögmann ; Mélanie Strauss ; Stanislav Sutovsky ; Gunhild Waldemar ; Bengt Winblad (2025): Letter to the Editor: Comment by European Alzheimer’s Disease Consortium (EADC) investigators on the negative recommendation of the CHMP on the marketing authorization of donanemab for early Alzheimer’ s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100259
LETTER TO THE EDITOR: BLOOD-BRAIN BARRIER WATER EXCHANGE AND PARAMAGNETIC SUSCEPTIBILITY ALTERATIONS DURING ANTI-AMYLOID THERAPY: PRELIMINARY MRI FINDINGS
Yuto Uchida, Yuya Kano, Hirohito Kan, Keita Sakurai, Hideyasu Morita, Yoshihiro Akagawa, Noriyuki Matsukawa, Kenichi Oishi
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CITATION:
Yuto Uchida ; Yuya Kano ; Hirohito Kan ; Keita Sakurai ; Hideyasu Morita ; Yoshihiro Akagawa ; Noriyuki Matsukawa ; Kenichi Oishi (2025): Letter to the Editor: Blood-brain barrier water exchange and paramagnetic susceptibility alterations during anti-amyloid therapy: preliminary MRI findings. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100256
EDITORIAL: TREATMENTS FOR ALZHEIMER’S AND THE DECLARATION OF HELSINKI
Timothy Daly, Andi Olluri, Markku Kurkinen
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CITATION:
Timothy Daly ; Andi Olluri ; Markku Kurkinen (2025): Editorial: Treatments for Alzheimer’s and the declaration of Helsinki. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100260
EARLY DETECTION OF ALZHEIMER’S DISEASE USING SMALL RNAS. RESULTS FROM THE EPAD COHORT
Tobias Sikosek, Marco Heuvelman, Jagoda Mika, Mustafa Kahraman, Julia Jehn, Maurice Frank, Alberto Daniel-Moreno, Jessika Ceiler, Jasmin Skottke, Marta Sanchez-Delgado, Patrick Neubert, Christina Rudolf, Kaja Tikk, Rastislav Horos, Jeffrey L. Cummings, Josie Butchart, Craig Ritchie, Jean Manson, Bruno R. Steinkraus, the EPAD consortium
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BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia, and early diagnosis is crucial to enable effective interventions. Currently, Alzheimer's disease is diagnosed through cognitive assessments, brain imaging and fluid biomarkers focused on determining amyloid (A) and, tau (T) protein levels as well as neurodegeneration (N) in the AT(N) framework. Prognostic biomarkers for predicting cognitive decline within the amyloid positive (Aβ+) individuals would further strengthen the framework.
OBJECTIVES: This study evaluated small RNAs as novel auxiliary biomarkers, independent of the AT(N) framework, either alone or in combination with established protein markers, for detecting the earliest cognitive decline in AD.
DESIGN: The European Prevention of Alzheimer’s Disease (EPAD) clinical trial platform is a prospective, multi-center study designed to investigate biomarkers for preclinical and prodromal AD.
SETTING: Peripheral whole blood RNA sequencing was performed on participants across Europe with no cognitive impairment or very mild cognitive impairment (MCI), stratified by cerebrospinal fluid amyloid levels.
PARTICIPANTS: 1,913 participants, 50 years or older and free of dementia diagnosis at enrollment, were analyzed.
INTERVENTION: (if any) Not applicable.
MEASUREMENTS: Ultra-deep small RNA sequencing was performed on whole blood samples using a refined blocking protocol to eliminate highly abundant erythroid small RNAs, and thereby to open sequencing bandwidth for the discovery of less abundant biomarker RNAs. Biomarker RNAs were deconvolved into plasma or blood cell origin and analyzed for functional relevance. We define high and low amyloid groups based on a cutoff on the p-tau181/Aβ1-42 ratio as determined from cerebrospinal fluid.
RESULTS: We identified a combination of small RNAs that predicted early cognitive decline (Clinical Dementia Rating of 0.5) with an area under the receiver-operator curve of ∼0.7. Notably, when focusing on individuals with cognitive decline and high amyloid burden (Aβ+), the predictive accuracy improved to an AUC of 0.77. This performance could be extended to the entire cohort when combining blood RNA and CSF amyloid markers (AUC 0.76). We conducted bioinformatic analyses to interrogate the likely functional relevance of these small RNAs, uncovering several links to dementia-relevant pathways, including neuronal, cardiovascular, and inflammatory activities. Our findings also suggest that small nucleolar RNAs warrant further investigation as potential disease-relevant markers, in addition to microRNAs.
CONCLUSIONS: Integrating small RNA biomarkers with protein-based assays offers preliminary evidence for stratifying MCI, particularly within the amyloid positive continuum. Small nucleolar RNAs and microRNAs warrant further exploration as complementary diagnostic tools, and their use may enable more precise and effective interventions.
CITATION:
Tobias Sikosek ; Marco Heuvelman ; Jagoda Mika ; Mustafa Kahraman ; Julia Jehn ; Maurice Frank ; Alberto Daniel-Moreno ; Jessika Ceiler ; Jasmin Skottke ; Marta Sanchez-Delgado ; Patrick Neubert ; Christina Rudolf ; Kaja Tikk ; Rastislav Horos ; Jeffrey L. Cummings ; Josie Butchart ; Craig Ritchie ; Jean Manson ; Bruno R. Steinkraus ; the EPAD consortium (2025): Early detection of Alzheimer’s disease using small RNAs. Results from the EPAD cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2025.100257
EDITORIAL : STRUCTURAL EQUATION MODELING CONFIRMS INTERACTION OF ALZHEIMER’S DISEASE AND VASCULAR DISEASE IN HIPPOCAMPAL INJURY
Gary A. Rosenberg
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CITATION:
Gary A. Rosenberg (2025): Editorial: Structural equation modeling confirms interaction of Alzheimer’s disease and vascular disease in hippocampal injury. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100255
TARGETING COGNITIVE AGING WITH CURCUMIN SUPPLEMENTATION: A SYSTEMATIC REVIEW AND META-ANALYSIS
Lirong Yu, Na Li, Bin Li, Kaisy Xinhong Ye, Jiuyu Guo, Jiatong Shan, Luwen Cao, Mei Song, Yanyu Wang, Tih-Shih Lee, Andrea B Maier, Lei Feng
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BACKGROUND: Cognitive aging is a growing public health concern, and curcumin, a bioactive compound derived from turmeric, has been proposed as a potential intervention to support cognitive function due to its anti-inflammatory and antioxidant properties.
OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the effects of curcumin on cognitive outcomes related to aging.
METHODS: A comprehensive search of PubMed, Embase, Cochrane Library, Web of Science, and Scopus was conducted to identify studies published up to June 18, 2024, including both in vivo preclinical animal studies and randomized controlled trials (RCTs) assessing curcumin's effects on cognitive function. In vivo animal studies using Alzheimer’s disease (AD) models and RCTs in human participants were included. Data were extracted and analyzed using meta-analytic techniques.
RESULTS: In preclinical in vivo murine studies (n = 25; total animals = 572), curcumin consistently improved both acquisition memory (SMD = -1.78, 95 % CI: -2.12 to -1.43) and retention memory (SMD = 2.36, 95 % CI: 1.72 to 3.00) in rodent models of AD. Ten human studies include 531 participants. Overall, curcumin showed no significant effect on global cognitive outcomes compared to placebo (SMD = 0.14, 95 % CI: -0.78 to 1.07). Subgroup analyses revealed significant improvements in working memory (SMD = 1.01, 95 % CI: 0.15 to 1.87) and processing speed (SMD = 0.37, 95 % CI: 0.07 to 0.67). The incidence of adverse events was higher in the curcumin group than in the control group.
CONCLUSIONS: Preclinical in vivo evidence suggests curcumin enhances cognitive function in AD models. However, human studies show inconsistent findings with benefits limited to specific cognitive domains. Larger, well-designed randomized controlled trials are needed to establish curcumin's efficacy and safety in cognitive aging.
CITATION:
Lirong Yu ; Na Li ; Bin Li ; Kaisy Xinhong Ye ; Jiuyu Guo ; Jiatong Shan ; Luwen Cao ; Mei Song ; Yanyu Wang ; Tih-Shih Lee ; Andrea B Maier ; Lei Feng (2025): Targeting cognitive aging with curcumin supplementation: A systematic review and meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100248
REPLY TO LETTER TO THE EDITOR: “REFINING THE EVIDENCE LINKING DIETARY DIVERSITY, GENETIC SUSCEPTIBILITY, AND DEMENTIA”
Boyue Zhao, Boyue Zhao
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CITATION:
Boyue Zhao ; Feng Zhang (2025): Reply to Letter to the Editor: “Refining the evidence linking dietary diversity, genetic susceptibility, and dementia”. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100246
LETTER TO THE EDITOR : REFINING THE EVIDENCE LINKING DIETARY DIVERSITY, GENETIC SUSCEPTIBILITY, AND DEMENTIA
Hongye Yao, Yangbo Lv
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CITATION:
Hongye Yao ; Yangbo Lv (2025): Letter to the Editor : Refining the evidence linking dietary diversity, genetic susceptibility, and dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100247
PSYCHOSOCIAL STRESSORS AND COGNITIVE FUNCTION: AN ANALYSIS USING DATA FROM THE ENGLISH LONGITUDINAL STUDY OF AGEING
Jiahao Li, Natalia Ortí-Casañ, Irem Bayraktaroglu, Giulia Mozzanica, Feng Zhang, Jocelien D.A. Olivier, Ulrich L.M. Eisel
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BACKGROUND: Growing evidence suggests that psychosocial stressors—such as financial strain, caregiving responsibilities, disability, and limiting long-term illnesses—may contribute to accelerated cognitive decline in older adults. However, the heterogeneity of stressor profiles and their distinct impact on specific cognitive domains remain poorly understood.
OBJECTIVE: To examine the associations between varying burdens of psychosocial stressors and cognitive function over a 10-year period using data from the English Longitudinal Study of Ageing (ELSA).
METHODS: We used longitudinal data from wave 4 (2008–2009) to wave 9 (2018–2019) of ELSA, comprising 10,893 participants aged ≥50 years at baseline who had valid measurements of psychosocial stressors and cognitive outcomes. Psychosocial stressors—financial strain, caregiving, disability, and limiting long-term illness—were assessed as binary indicators and summed into three categories (No Stressors, One Stressor, Multiple Stressors). Cognitive function was assessed using an overall global cognition score and scores of three specific domains: memory, executive function, and orientation. Baseline associations were examined via multiple linear regression, while linear mixed-effects models evaluated longitudinal trajectories of cognitive change. All models were progressively adjusted for demographic, lifestyle, and clinical covariates.
RESULTS: At baseline, participants reporting multiple stressors (18.2 % of the sample) had significantly lower global cognitive and executive function scores compared to those with no stressors (43.3 %). Over the 10-year follow-up, a higher stress burden predicted faster declines in global cognition, memory, and executive function. These associations remained robust after adjusting for sociodemographic characteristics, health behaviors, and chronic conditions. Random intercept and random slope models yielded consistent findings, indicating a dose–response relationship between stress burden and cognitive deterioration.
CONCLUSION: Older adults experiencing multiple psychosocial stressors face an elevated risk of both lower initial cognitive function and accelerated decline over time. These findings underscore the importance of identifying and mitigating modifiable stressors—such as financial strain and caregiving demands—to potentially preserve cognitive health in later life. Interventions tailored to individuals with higher stress burdens may be especially beneficial in slowing cognitive deterioration.
CITATION:
Jiahao Li ; Natalia Ortí-Casañ ; Irem Bayraktaroglu ; Giulia Mozzanica ; Feng Zhang ; Jocelien D.A. Olivier ; Ulrich L.M. Eisel (2025): Psychosocial stressors and cognitive function: An analysis using data from the English longitudinal study of ageing. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100232
TAILORING MULTIDOMAIN INTERVENTION PROGRAMS TO REDUCE COGNITIVE AND PHYSICAL DECLINE IN OLDER ADULTS: EXAMINING RURAL-URBAN DIFFERENCES IN A NATIONWIDE CLUSTER-RANDOMIZED CONTROLLED TRIAL
Min-Yin Ho, Wei-Ju Lee, Ko-Han Yen, Chih-Kuang Liang, Li-Ning Peng, Ming-Hsien Lin, Ching-Hui Loh, Fei-Yuan Hsiao, Liang-Kung Chen
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BACKGROUND: Frailty and cognitive impairment are major challenges in aging populations. Multidomain interventions targeting physical, cognitive, and nutritional health show promise; however, evidence on rural-urban differences in efficacy remains limited.
OBJECTIVES: To evaluate the impact of rural-urban disparities on the clinical efficacy of a 12-month multidomain intervention for cognitive and physical outcomes in older adults.
DESIGN: Cluster-randomized controlled trial.
SETTING: Community clusters in five cities/counties across Taiwan.
PARTICIPANTS: A total of 1082 adults aged ≥65 years from 40 community clusters were randomized to intervention or control groups.
INTERVENTION: The intervention group received a 12-month program including physical exercise (45 min/session), cognitive training (1 hour/session), and nutritional guidance (15 min/session). The control group received telephone-based health education. This trial was registered at ClinicalTrials.gov (NCT03056768)
MEASUREMENTS: Outcomes included walking speed, grip strength, physical activity (METs), frailty (CHS score), and cognitive function (MoCA), assessed at baseline, 6, and 12 months.
RESULTS: Urban participants showed significantly greater gains in visuospatial/executive function at the 12 month (rural-urban difference 0.63, 95 % CI: 0.26 -1.03), and walking speed at the 12 month (rural-urban difference 0.12 m/s, 95 % CI: 0.05 – 0.19). Rural participants demonstrated better improvements in grip strength at the 12 month (rural-urban difference -2.59 kg, 95 % CI: -3.91 - -1.27) and language function (rural-urban difference -0.38, 95 % CI: -0.68 - -0.09). Frailty reduction was more pronounced in urban areas at the 12 month (−0.21, 95 % CI: -0.38 - -0.03, p = 0.025), but showed minimal change in the rural participants.
CONCLUSION: Rural-urban disparities influence the effectiveness of multidomain interventions. Tailored strategies are needed to optimize health outcomes across diverse settings.
CITATION:
Min-Yin Ho ; Wei-Ju Lee ; Ko-Han Yen ; Chih-Kuang Liang ; Li-Ning Peng ; Ming-Hsien Lin ; Ching-Hui Loh ; Fei-Yuan Hsiao ; Liang-Kung Chen (2025): Tailoring multidomain intervention programs to reduce cognitive and physical decline in older adults: Examining rural-urban differences in a nationwide cluster-randomized controlled trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100231
THE COUPLING OF GLOBAL BRAIN ACTIVITY AND CEREBROSPINAL FLUID FLOW AS A POTENTIAL PREDICTIVE MARKER OF BRAIN AMYLOID-Β ACCUMULATION
Yuya Tanaka, Koji Kamagata, Yuya Saito, Kaito Takabayashi, Rinako Iseki, Wataru Uchida, Christina Andica, Akifumi Hagiwara, Akihiko Wada, Toshiaki Akashi, Osamu Abe, Shigeki Aoki, Alzheimer’s Disease Neuroimaging Initiative
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BACKGROUND: Impaired cerebrospinal fluid (CSF) clearance is thought to contribute to amyloid-β (Aβ) accumulation in Alzheimer’s disease (AD). Global brain activity–CSF flow coupling (gBOLD–CSF coupling), measured through resting-state functional MRI, reflects CSF clearance capacity. A higher coupling value indicates weaker coupling. Its potential as a predictive marker for Aβ accumulation remains unclear.
OBJECTIVES: This study aims to determine whether weaker gBOLD–CSF coupling precedes Aβ accumulation in cognitively normal, Aβ-negative individuals and to explore its predictive potential for amyloid conversion.
DESIGN: A longitudinal observational study using Alzheimer’s Disease Neuroimaging Initiative (ADNI) data.
SETTING: Data from ADNI-participating sites.
PARTICIPANTS: 16 cognitively normal participants, initially Aβ-negative: seven fast-converters (transitioned to Aβ-positive within two years) and nine slow-converters (remained Aβ-negative for at least two years).
MEASUREMENTS: gBOLD–CSF coupling was calculated as the Pearson correlation coefficient between global Blood-Oxygen-Level-Dependent (BOLD) and CSF inflow signals. Group differences in gBOLD–CSF coupling were analyzed, along with partial correlation analyses between gBOLD–CSF coupling and annual changes in Aβ biomarkers and cognitive scores.
RESULTS: Fast-converters showed significantly higher gBOLD–CSF coupling values, indicating weaker coupling (Cohen’s d = 1.76, p = 0.012). Coupling values positively correlated with annual changes in Aβ-PET SUVR (r = 0.594, p = 0.054) and negatively with MoCA scores (r = −0.654, p = 0.021).
CONCLUSION: Weaker gBOLD–CSF coupling precedes brain Aβ accumulation, indicating its potential as a predictive marker for amyloid conversion. Future studies should refine clinical thresholds for early intervention strategies in AD prevention.
CITATION:
Yuya Tanaka ; Koji Kamagata ; Yuya Saito ; Kaito Takabayashi ; Rinako Iseki ; Wataru Uchida ; Christina Andica ; Akifumi Hagiwara ; Akihiko Wada ; Toshiaki Akashi ; Osamu Abe ; Shigeki Aoki ; Alzheimer’s Disease Neuroimaging Initiative (2025): The coupling of global brain activity and cerebrospinal fluid flow as a potential predictive marker of brain amyloid-β accumulation. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100228
IMPACT OF CARDIOVASCULAR RISK FACTORS ON PLASMA BIOMARKERS IN PREDICTION OF ALZHEIMER\'S AND CEREBROVASCULAR NEUROPATHOLOGY
Camilo Bermudez, Jeremy A. Syrjanen, Nikki H. Stricker, Alicia Algeciras-Schimnich, Naomi Kouri, Walter K. Kremers, Ronald C. Petersen, Clifford R. Jack Jr, David S. Knopman, Dennis W. Dickson, Darren M. Rothberg, Christina M. Moloney, Baayla D.C. Boon, Aivi T. Nguyen, R. Ross Reichard, Melissa E. Murray, Michelle M. Mielke, Prashanthi Vemuri, Jonathan Graff-Radford
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BACKGROUND: Plasma biomarkers for Alzheimer’s disease and neurodegeneration have shown accurate prediction of underlying neuropathology. However, chronic cardiovascular risk factors such as diabetes and hypertension are associated with plasma biomarker levels and can influence the accurate prediction of underlying neuropathologic changes.
OBJECTIVE: To understand the interaction between plasma biomarkers of Alzheimer’s disease and neurodegeneration with cardiovascular risk factors in relation to neuropathologic change in a heterogenous population to ascertain a more accurate utilization of these biomarkers.
DESIGN: Retrospective, case-control study.
SETTING: Population-based, Olmstead county, Minnesota, USA.
PARTICIPANTS: Three-hundred and fifty-one participants (aged 87.4 ± 7.5 years) with brain autopsy and antemortem plasma biomarker testing.
MEASUREMENTS: Plasma biomarker testing for Aβ42/40, p-tau181, GFAP, and NfL using Quanterix Simoa assays. Cardiovascular risk factors were quantified by a composite score of cardiovascular metabolic conditions (CMC) consisting of a binary history of diabetes, congestive heart failure, stroke, coronary artery disease, atrial fibrillation, hypertension, or dyslipidemia. Plasma biomarkers and cardiovascular metabolic conditions score were Z-scored and neuropathologic scales were binarized into high and low categories. Outcomes included elevated microvascular (Kalaria) and macrovascular (Strozyk) neuropathologic scales as well as Alzheimer’s disease neuropathologic change (ADNC), Thal phase, Braak stage, and neuritic plaque score. Multivariate logistic regression models incorporated interaction terms between plasma biomarkers and CMC while controlling for age, sex, cognitive impairment, and BMI.
RESULTS: We observed that at higher cardiovascular metabolic conditions score, the association between GFAP and overall ADNC (OR = 0.61 [0.42, 0.89]), Thal phase (OR = 0.48 [0.33, 0.71]), and Braak Stage (OR = 0.56 [0.37, 0.84]), became weaker, while the association with Strozyk score (OR = 1.65 [1.11, 2.46]) was stronger with higher CMC. Meanwhile, at higher CMC Aβ42/40 became more strongly negative with high Braak stage (OR = 0.63 [0.47, 0.85]), neuritic plaque score (OR 0.70 [0.52, 0.95]), Kalaria score (OR = 0.71 [0.57, 0.88]), and Strozyk score (OR = 0.60 [0.43, 0.83]). The association between p-tau181 and Thal phase (OR = 1.43 [1.00, 2.04]) was stronger at higher CMC while the association between p-tau181 and Strozyk score (OR = 0.47 [0.31, 0.71]) was weaker at higher CMC. There was no interaction between NfL and CMC score for any metric of neuropathologic change.
CONCLUSION: Understanding how cardiovascular risk factors can modulate plasma biomarkers is important for their interpretation with respect to underlying pathology and their clinical application in screening, diagnosis, and prognosis of neurodegenerative diseases.
CITATION:
Camilo Bermudez ; Jeremy A. Syrjanen ; Nikki H. Stricker, ; Alicia Algeciras-Schimnich ; Naomi Kouri ; Walter K. Kremers ; Ronald C. Petersen ; Clifford R. Jack Jr ; David S. Knopman ; Dennis W. Dickson ; Darren M. Rothberg ; Christina M. Moloney ; Baayla D.C. Boon ; Aivi T. Nguyen ; R. Ross Reichard ; Melissa E. Murray ; Michelle M. Mielke ; Prashanthi Vemuri ; Jonathan Graff-Radford (2025): Impact of cardiovascular risk factors on plasma biomarkers in prediction of Alzheimer's and cerebrovascular neuropathology. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.1002248
ADHERENCE TO AN ANTI-INFLAMMATORY DIET IS ASSOCIATED WITH LOWER ALZHEIMER’S DISEASE MORTALITY: A MODIFIABLE RISK FACTOR IN A NATIONAL COHORT
Ching-Chi Hsu, Shiow-Ing Wang, Sebastian Yu, Eric S. Lin, James Cheng-Chung Wei
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BACKGROUND: Chronic neuroinflammation contributes to Alzheimer’s disease (AD) pathogenesis, and diet is a modifiable factor influencing inflammation. The impact of an anti-inflammatory diet on AD-specific mortality remains unclear.
OBJECTIVES: To examine the association between adherence to an anti-inflammatory diet (measured as the percentage of dietary energy from anti-inflammatory foods) and AD-specific mortality, as well as all-cause mortality, in a large national cohort, and to determine whether associations differ by sex or race/ethnicity.
METHODS: We analyzed 18,795 U.S. adults (≥18 years) from the 2007–2014 National Health and Nutrition Examination Survey. Anti-inflammatory diet adherence was defined as the percentage of total energy intake from anti-inflammatory foods, categorized as 0 %, <5 %, 5–9.99 %, or ≥10 %. Outcomes were AD-specific mortality and all-cause mortality ascertained via the National Death Index. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for mortality across intake categories, adjusting for demographic, lifestyle, and health factors. Analyses were stratified by sex, race/ethnicity, and age (≥45 years for AD mortality).
RESULTS: Participants with 0 % anti-inflammatory intake had a higher all-cause mortality risk (HR 3.82, 95 % CI 1.18–12.33) compared to those with ≥10 % intake. In the overall analysis, 0 % anti-inflammatory intake showed a trend of reduced AD-specific mortality although its did not reach statistical significance after full adjustment (HR 3.04, 95 % CI 0.74–12.46 vs. ≥10 % intake; p>0.05). Notably, the inverse association between anti-inflammatory diet and AD mortality emerged in subgroup analyses. Male participants and non-Hispanic White participants with 0 % intake had the highest AD mortality hazards (HR 12.83 and 3.77, respectively, vs. ≥10 % intake), indicating significant risk reductions with anti-inflammatory diet in these groups. In contrast, no significant associations were observed in female or non-White subgroups. Even a modest intake of anti-inflammatory foods (≥10 % of calories) was associated with lower AD mortality risk in the above subgroups and with lower all-cause mortality overall.
CONCLUSION: Greater consumption of anti-inflammatory foods was associated with lower all-cause and a trend toward lower AD-specific mortality. The observed protective effects were confined to certain subpopulations (notably men and non-Hispanic Whites). Even a small portion of the diet (10 % of calories) being anti-inflammatory was linked to reduced mortality risk in these groups, suggesting that achievable dietary changes could have an impact. These findings support modifying dietary content is a practical, low-cost intervention that could mitigate neuroinflammation to reduce AD mortality risk.
CITATION:
Ching-Chi Hsu ; Shiow-Ing Wang ; Sebastian Yu ; Eric S. Lin ; James Cheng-Chung Wei (2025): Adherence to an anti-inflammatory diet is associated with lower Alzheimer’s disease mortality: A modifiable risk factor in a national cohort. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100221
HOUSEHOLD FUEL USE AND MOTORIC COGNITIVE RISK SYNDROME AMONG OLDER ADULTS: EVIDENCE FROM COHORT STUDY AND LIFE COURSE ANALYSIS
Guanghui Cui, Shaojie Li, Weiwei Li, Xuezhi Zhang
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BACKGROUND: Motoric cognitive risk syndrome (MCRS) is a predementia syndrome, and its prevention is valuable for reducing the incidence of dementia. However, few studies have focused on the association between indoor air pollution caused by household cooking fuel use and MCRS. This study aimed to investigate whether clean cooking fuel use is associated with reduced MCRS risk and whether the timing of clean fuel adoption across the life span is associated with MCRS prevalence.
METHODS: We used data from the China Health and Retirement Longitudinal Study. A prospective cohort analysis (n = 4251) examined baseline fuel use (2011) and incident MCRS over four years. A cross-sectional life course analysis (n = 6964) linked retrospective fuel use histories (2014 life history survey) to MCRS status in 2015. Modified Poisson regression was used to estimate relative risks (RRs) and 95 % confidence intervals (CIs), adjusting for covariates.
RESULTS: In the cohort study, clean fuel use at baseline was associated with a reduced risk of MCRS (RR = 0.76; 95 % CI: 0.61–0.96). Lower risks were also observed among participants who transitioned from solid to clean fuels and those who consistently used clean fuels. In the life course analysis, clean fuel adoption in early or middle adulthood was linked to lower MCRS prevalence.
CONCLUSION: Clean fuel use for cooking and transitioning from solid to clean fuels decreases MCRS risk among older adults. Moreover, earlier adoption of clean cooking fuels is associated with a lower prevalence of MCRS in later life.
CITATION:
Guanghui Cui ; Shaojie Li ; Weiwei Li ; Xuezhi Zhang (2025): Household fuel use and motoric cognitive risk syndrome among older adults: Evidence from cohort study and life course analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100227
BRIDGING THE GAP: A CONVERSION FRAMEWORK FOR CDR-SB AND MOCA SCORES IN ALZHEIMER\'S DISEASE AND RELATED DEMENTIA
Babak Haji, Quanwu Zhang, Amir Abbas Tahami Monfared
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BACKGROUND: Accurate assessment of cognitive impairment is essential to effective Alzheimer’s disease (AD) management and research. However, the absence of validated methods to translate scores between widely used instruments—such as the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) in trials and the Montreal Cognitive Assessment (MoCA) in clinical practice—poses a significant barrier. This limits data harmonization, impedes cross-study comparability, and complicates the integration of clinical and research evidence. Bridging this gap is critical for consistent staging, longitudinal monitoring, and data-driven decision-making in AD and related dementias.
OBJECTIVES: To develop and validate bidirectional score conversion tables between CDR-SB and MoCA using a large, diverse cohort spanning the full spectrum of cognitive function.
DESIGN: Retrospective, cross-sectional analysis using equipercentile equating with log-linear smoothing. Optimal smoothing parameters were selected by minimizing mean squared error, Akaike Information Criterion, and Bayesian Information Criterion. Concordance was assessed using Spearman’s rank correlation and Bland-Altman plots.
SETTING: National Alzheimer’s Coordinating Center (NACC), aggregating standardized assessments from 35 U.S.-based Alzheimer’s Disease Research Centers.
PARTICIPANTS: 23,717 individuals (59,871 visits) with same-day CDR-SB and MoCA assessments from January 2015 to September 2024, spanning normal cognition, mild cognitive impairment (MCI), and dementia.
INERVENTION: None; this was a secondary analysis of existing data.
MEASUREMENTS: Primary measures included CDR-SB (0–18; higher = greater impairment) and MoCA (0–30; higher = better cognition). Bidirectional crosswalk tables were derived using equipercentile equating.
RESULTS: CDR-SB and MoCA scores showed strong inverse correlation (Spearman’s ρ = –0.68; p < 0.001). Crosswalk tables demonstrated good agreement across the cognitive spectrum and performed consistently in the full cohort and an AD-specific subgroup.
CONCLUSIONS: This study provides the first validated, bidirectional CDR-SB–MoCA crosswalk, supporting data harmonization and consistent interpretation of cognitive severity across research and clinical settings.
CITATION:
Babak Haji ; Quanwu Zhang ; Amir Abbas Tahami Monfared (2025): Bridging the gap: A conversion framework for CDR-SB and MoCA scores in Alzheimer's disease and related dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2025.8
TRAJECTORIES OF CARDIORESPIRATORY FITNESS MEASURED BY METABOLIC EQUIVALENTS AND THE RISK OF ALZHEIMER\'S AND RELATED DEMENTIAS
Edward Zamrini, Yan Cheng, Peter Kokkinos, Charity J Morgan, Charles Faselis, Helen M Sheriff, Yijun Shao, Xuemei Sui, Ali Ahmed, Qing Zeng
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BACKGROUND: Higher fitness levels have been reported to protect against Alzheimer's Disease and Related Dementias (ADRD). However, the association between changes in fitness over time and ADRD risk remains unknown. This study aims to identify clusters of metabolic equivalents (METs) trajectories and examine their correlation with incident ADRD.
METHODS: A retrospective cohort study was conducted among Veterans with ≥3 standardized exercise treadmill tests (ETT) between 2000 and 2017. The exposure was change in fitness expressed in metabolic equivalents (METs). METs are based on treadmill speed, grade, and time. One MET is equivalent to 3.5 ml per kg of body weight per minute. The outcome was incident ADRD after the final ETT test, identified by diagnosis codes. Standardized METs scores were generated using mean and standard deviation for each age and sex stratum. Latent class growth analysis (LCGA) identified trajectory clusters. We assessed the association between clusters and ADRD using unadjusted Kaplan-Meier curves (overall and by age groups) and a multivariate Cox regression model adjusted for baseline characteristics at the first ETT.
RESULTS: A total of 75,851 veterans were included. The average number of ETTs was 4.0 ± 1.8, with the average time gap of 6.5 ± 3.8 years between first and last test. We identified five trajectory clusters: Group 1 (n = 22,485), Group 2 (n = 22,694), Group 3 (n = 6691), Group 4 (n = 19,386), and Group 5 (n = 4595). All groups, except for Group 3, showed a stable and slight improvement or decline over time, differing only in their initial standardized METs scores: Group 5 had the highest initial score, Group 1 had the lowest initial score, while Group 3 started out with a score almost as high as Group 4 and dropped to as low as Group 1. Compared to Group 1, Group 3 had a 12 % reduced risk of developing ADRD (HR = 0.88; 95 % CI: 0.77 – 1.01; p = 0.0660), with a greater reduction than Group 2 (10 %) but less than Group 4 (17 %) or Group 5 (24 %).
DISCUSSION: Our findings underscore the potential benefits of maintaining fitness to reduce the risk of ADRD with age. Although declining fitness levels are associated with an increased risk, the initial higher baseline fitness provides a degree of ongoing protection against ADRD.
CITATION:
Edward Zamrini ; Yan Cheng ; Peter Kokkinos ; Charity J Morgan ; Charles Faselis ; Helen M Sheriff ; Yijun Shao ; Xuemei Sui ; Ali Ahmed ; Qing Zeng (2025): Trajectories of Cardiorespiratory Fitness Measured by Metabolic Equivalents and the Risk of Alzheimer's and Related Dementias. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100222
BISPECIFIC BRAIN-PENETRANT ANTIBODIES FOR TREATMENT OF ALZHEIMER’S DISEASE
Dag Sehlin, Greta Hultqvist, Wojciech Michno, Ximena Aguilar, Amelia D Dahlén, Enrica Cerilli, Nadja M Bucher, Sara Lopes van den Broek, Stina Syvänen
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The emerging class of bispecific antibodies represents a significant advancement in Alzheimer’s disease (AD) immunotherapy by addressing the limited brain concentrations achieved with conventional monoclonal antibodies. The majority of bispecific antibodies developed for AD treatment utilize transferrin receptor (TfR1)-mediated transcytosis to enhance blood-brain barrier (BBB) penetration, resulting in higher and more uniform brain concentrations compared to conventional antibodies. This improved delivery has demonstrated superior efficacy in reducing brain amyloid-beta (Aβ) burden. Additionally, TfR1-mediated delivery may help mitigate adverse effects such as amyloid-related imaging abnormalities (ARIA). This is likely achieved by a reduction in antibody accumulation at vascular Aβ deposits, resulting from the combined effects of lower dosing and a different brain entry route when using bispecific antibodies. Besides targeting Aβ, bispecific antibodies have been engineered to address other key pathological features of AD, including tau pathology and neuroinflammatory targets, which are critical drivers of disease progression. These antibodies also show promise in diagnostic applications, particularly as radioligands for antibody-based positron emission tomography (immunoPET), leveraging their rapid brain delivery and efficient and specific target engagement. Moreover, the principles of bispecific antibody technology have been adapted for use beyond immunotherapy. The incorporation of TfR1-binding domains into enzymes, antisense oligonucleotides, or viral vectors such as adeno-associated viruses broadens their therapeutic potential. These approaches may enable more efficient treatment strategies, not only for AD but also for other neurological disorders, by facilitating the delivery of diverse therapeutic agents across the BBB.
CITATION:
Dag Sehlin ; Greta Hultqvist ; Wojciech Michno ; Ximena Aguilar ; Amelia D Dahlén ; Enrica Cerilli ; Nadja M Bucher ; Sara Lopes van den Broek ; Stina Syvänen (2025): Bispecific brain-penetrant antibodies for treatment of Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2025.8
CEREBROVASCULAR DISEASE IN ALZHEIMER\'S DISEASE: BRAIN STRUCTURE AS A CRITICAL MEDIATOR OF COGNITIVE DECLINE
Chao Tang, Yaqi Ding, Jiaxin Yang, Dian He
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BACKGROUND: The co-occurrence of Alzheimer's disease and cerebrovascular disease is increasingly prevalent in aging populations, yet the mechanisms of their interaction remain incompletely understood. This study aims to investigate the associations between CVD and AD and their composite effects on cognitive function, identifying key mediating pathways in these relationships.
METHODS: Participants underwent standardized clinical evaluations, detailed neuropsychological testing, and comprehensive neuropathological examinations. Structural equation modeling with multiple mediation analyses was employed to disentangle direct and indirect effects of vascular pathology on cognition and identify key mediating pathways. Relationships between specific cognitive domain assessments and whole brain and hippocampal volumes were analyzed, while interactions between traditional AD biomarkers (amyloid, tau) and vascular factors were examined.
RESULTS: CVD substantially increased AD risk. Structural equation modeling revealed that vascular factors influence cognitive performance primarily through hippocampal atrophy, APOE genotype, and cerebral atrophy. Participants with concomitant AD +CVD pathology displayed a distinctive hybrid pattern of brain-cognition relationships, with stronger correlations between hippocampal atrophy and cognitive performance compared to pure AD or CVD cases. Pathway-specific analysis demonstrated that hippocampal atrophy served as the strongest mediator of vascular effects on cognition, followed by cerebral atrophy and APOE genotype.
CONCLUSION: Our findings demonstrate that cerebrovascular disease significantly increases the risk of Alzheimer's disease and substantially influences its clinical expression through multiple pathways, with structural brain changes serving as critical mediators of vascular effects on cognition. These results highlight the importance of addressing vascular health as an integral component of strategies to prevent and treat Alzheimer's disease and related cognitive disorders.
CITATION:
Chao Tang ; Yaqi Ding ; Jiaxin Yang ; Dian He (2025): Cerebrovascular disease in Alzheimer's disease: Brain structure as a critical mediator of cognitive decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100209
CAUSAL RELATIONSHIP AND MEDIATING ROLE BETWEEN DEPRESSION AND COGNITIVE PERFORMANCE
Xinyu Hao, Fuyang Cao, Ziyao Xu, Shaohua You, Tianyue Mi, Lei Wang, Yongxin Guo, Zhuoning Zhang, Jiangbei Cao, Jingsheng Lou, Yanhong Liu, Xianyang Chen, Zhikang Zhou, Weidong Mi, Li Tong
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BACKGROUND: Recent studies have increasingly emphasized the robust correlation between depression and cognitive function. However, it remains unclear whether this relationship is causal or merely coincidental. To address this uncertainty, we conducted two-sample bidirectional Mendelian randomization (MR) analyses to investigate the connection between depression and cognitive performance.
METHODS: We sourced genome-wide association study (GWAS) data for depression (NSNPs=21,306,230) from the FinnGen (R10) and for cognitive performance (NSNPs=10,049,954) from the IEU GWAS database. Causal effects employed methodologies such as Inverse variance weighted (IVW), weighted median, MR Egger, simple mode and weighted mode. Two-step analysis determined the contribution of the mediator variable to the outcomes. To determine stability and reliability, sensitivity analyses were performed that included an assessment of heterogeneity, horizontal pleiotropy, and the leave-one-out techniques.
RESULTS: This MR analysis identified 8 independent significant SNPs associated with depression and 81 SNPs linked to cognitive performance. Our findings revealed that depression increases the risk of developing deteriorating cognitive performance (IVW β, -0.11; 95 % confidence interval (CI), -0.18 – -0.05; PIVW value= 5.97E-04). Conversely, cognitive performance decline could also predispose individuals to depression [odds ratio (OR)IVW, 0.85; 95 % CI, 0.76 – 0.95; PIVW value=0.004]. Multivariate MR analysis confirmed the robustness of this bidirectional association. A two-step MR mediation analysis indicated that the pathway from depression to cognitive performance is mediated by pain, with a mediation effect size of -0.022 and a mediation ratio of 28.95 %. The pathway from cognitive performance to depression is mediated by frailty, with a mediation effect value of -0.028, representing 22.40 % of the mediation proportion.
CONCLUSION: A two-way causal relationship between depression and cognitive performance, with pain and frailty being mediating factors, respectively. Future research should prioritize mechanistic studies, targeted interventions, and personalized approaches to disentangle and mitigate the bidirectional effects of depression and cognitive performance.
CITATION:
Xinyu Hao ; Fuyang Cao ; Ziyao Xu ; Shaohua You ; Tianyue Mi ; Lei Wang ; Yongxin Guo ; Zhuoning Zhang ; Jiangbei Cao ; Jingsheng Lou ; Yanhong Liu ; Xianyang Chen ; Zhikang Zhou ; Weidong Mi ; Li Tong (2025): Causal relationship and mediating role between depression and cognitive performance. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100196
JPAD Volume 12, N°07 - 2025
EDITORIAL: ASTROCYTES PROVIDE A UNIQUE BIOMARKER FOR ALZHEIMER’S AND OTHER PATHOLOGIES
Eric Siemers
J Prev Alz Dis 2025;7(12)
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CITATION:
Eric Siemers (2025): Editorial: Astrocytes provide a unique biomarker for Alzheimer’s and other pathologies. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100233
EDITORIAL: BREAKING BARRIERS: DELIVERING THERAPEUTICS TO THE BRAIN IN ALZHEIMER’S DISEASE
Bart De Strooper, Philip Scheltens, Stephen Salloway
J Prev Alz Dis 2025;7(12)
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CITATION:
Bart De Strooper ; Philip Scheltens ; Stephen Salloway (2025): Editorial: Breaking barriers: Delivering therapeutics to the brain in Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100229
EDITORIAL: EXERCISE FOR DEMENTIA PREVENTION: EVIDENCE FOR A FLEXIBLE PRESCRIPTION
Mikel Izquierdo
J Prev Alz Dis 2025;7(12)
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CITATION:
Mikel Izquierdo (2025): Editorial: Exercise for dementia prevention: Evidence for a flexible prescription. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100249
EDITORIAL: PHYSICAL ACTIVITY AND ALZHEIMER’S DISEASE: A CALL FOR EVIDENCE INCORPORATION
Juan Luis Sánchez-Sánchez, Philipe de Souto Barreto
J Prev Alz Dis 2025;7(12)
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CITATION:
Juan Luis Sánchez-Sánchez ; Philipe de Souto Barreto (2025): Physical activity and Alzheimer’s disease: a call for evidence incorporation. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100225
EDITORIAL: SERUM BDNF AND PROGRESSION TO MCI IN COGNITIVELY NORMAL OLDER ADULTS A PROSPECTIVE COHORT STUDY
Gary A. Rosenberg
J Prev Alz Dis 2025;7(12)
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CITATION:
Gary A. Rosenberg (2025): Editorial: Serum BDNF and progression to MCI in cognitively normal older adults A prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100254
UTILITY OF PLASMA GFAP AS A SECONDARY ENDPOINT FOR CLINICAL TRIALS IN ALZHEIMER’S DISEASE
Sarah Abbas, Pamela C. L Ferreira, Bruna Bellaver, Guilherme Povala, Guilherme Povala, Cristiano Schaffer Aguzzoli, Hussein Zalzale, João Pedro Ferrari-Souza, Douglas T. Leffa, Firoza Z. Lussier, Carolina Soares, Guilherme Bauer-Negrini, Markley Silva Oliveira-Junior, Matheus Scarpatto Rodrigues, Pampa Saha, Emma Ruppert, Marina Scop Medeiros, Cécile Tissot, Joseph Therriault, Nesrine Rahmouni, Stijn Servaes, Andrea L. Benedet, Nicholas J. Ashton, Dana L. Tudorascu, Serge Gauthier, Helmet Karim, Chang Hyung Hong, Hyun Woong Roh, Eduardo R Zimmer, Thomas K. Karikari, Henrik Zetterberg, Kaj Blennow, Anum Saeed, Sang Joon Son, Pedro Rosa-Neto, Tharick Pascoal, for Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: Clinical trials have recently incorporated plasma glial fibrillary acidic protein (GFAP) as an exploratory endpoint. To include plasma GFAP as a secondary endpoint, it is essential to characterize its longitudinal progression in target populations.
OBJECTIVE: To evaluate the potential use of plasma GFAP changes as a secondary endpoint in Alzheimer’s disease trials.
METHODS: We longitudinally evaluated plasma GFAP in individuals with amyloid-beta (Aβ)-PET scans at baseline in three well-characterized cohorts. Cox proportional hazards regression tested the association between changes in plasma GFAP and cognitive function. Analysis of the 95 % confidence interval of annualized change in plasma GFAP provided statistical inference for a significant longitudinal change. Effect size was calculated as the group mean divided by the standard deviation (SD). We estimated the sample size needed to test a 25% drug effect with 80% power on reducing changes in GFAP.
RESULTS: We assessed 487 individuals [176 cognitively unimpaired (CU; 29% Aβ positive) and 311 cognitively impaired (CI; 51% Aβ positive)] with some degree of cerebrovascular disease (Fazekas 1–3), over a mean (SD) follow-up of 1.84 (0.46) years. Changes in plasma GFAP were significantly associated with worsening in Clinical Dementia Rating sum of boxes (CDR-SB) score across the population (p < 0.0001). In CU, only Aβ positive individuals showed significant changes in GFAP (p < 0.001). On the other hand, both CI Aβ positive and negative individuals showed longitudinal progression in GFAP levels (p < 0.0001). The effect size of changes in plasma GFAP was higher in CU Aβ positive (0.44), followed by CI Aβ positive (0.42) and CI Aβ negative (0.38). Clinical trials focusing on CU Aβ positive would require 1320 individuals per study arm, while focusing on CI Aβ positive would require 1440 individuals per study arm.
CONCLUSION: Plasma GFAP increased in parallel with cognitive decline, making it a candidate for monitoring disease progression in trials aimed at mitigating cognitive deterioration. Although Aβ positivity significantly accelerated GFAP progression, the fact that GFAP was increased in CI Aβ negative with cerebrovascular disease supports its potential use as a secondary endpoint in this population as well.
CITATION:
Sarah Abbas ; Pamela C. L Ferreira ; Bruna Bellaver ; Guilherme Povala ; Francieli Rohden ; Cristiano Schaffer Aguzzoli ; Hussein Zalzale ; João Pedro Ferrari-Souza ; Douglas T. Leffa ; Firoza Z. Lussier ; Carolina Soares ; Guilherme Bauer-Negrini ; Markley Silva Oliveira-Junior ; Matheus Scarpatto Rodrigues ; Pampa Saha ; Emma Ruppert ; Marina Scop Medeiros ; Cécile Tissot ; Joseph Therriault ; Nesrine Rahmouni ; Stijn Servaes ; Andrea L. Benedet ; Nicholas J. Ashton ; Dana L. Tudorascu ; Serge Gauthier ; Helmet Karim ; Chang Hyung Hong ; Hyun Woong Roh ; Eduardo R Zimmer ; Thomas K. Karikari ; Henrik Zetterberg ; Kaj Blennow ; Anum Saeed ; Sang Joon Son ; Pedro Rosa-Neto ; Tharick Pascoal ; for Alzheimer’s Disease Neuroimaging Initiative (2025): Utility of plasma GFAP as a secondary endpoint for clinical trials in Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100205
DRUG DELIVERY STRATEGIES TO CROSS THE BLOOD-BRAIN BARRIER IN ALZHEIMER’S DISEASE: A COMPREHENSIVE REVIEW ON THREE PROMISING STRATEGIES
Lotte A. de Koning, Daniel A. Vazquez-Matias, Wissam Beaino, Daniëlle J. Vugts, Guus A.M.S. van Dongen, Wiesje M. van der Flier, Mario Ries, Dannis G. van Vuurden, Everard G.B. Vijverberg, Elsmarieke van de Giessen
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryThe field of Alzheimer’s disease (AD) drug development is rapidly changing, with two anti-amyloid monoclonal antibodies (mAbs) having received Food and Drug Administration (FDA) approval, additionally many compounds are in the pipeline. A major obstacle for novel AD therapeutics is the blood-brain barrier (BBB), which restricts passage of particles larger than 400–500 Da. It is estimated that only ∼1 % of mAbs, being ∼150 kDa, passes the BBB, which greatly hampers the efficacy of treatment. To enhance treatment efficacy and to lower the drug dose needed, mechanisms that effectively increase drug delivery across the BBB are urgently sought for. This narrative review describes three promising strategies to enhance drug delivery across the BBB in AD: focused ultrasound (FUS) with microbubbles, receptor-mediated transcytosis (RMT) and delivery using nanoparticle carrier systems. FUS and RMT have shown promising preclinical results and are now being tested in humans whereas nanoparticle carrier systems still need further preclinical validation before clinical application in humans. 89Zr-Immuno-PET provides a unique opportunity to noninvasively monitor and quantitatively assess novel brain delivery methods.
CITATION:
Lotte A. de Koning ; Daniel A. Vazquez-Matias ; Wissam Beaino ; Daniëlle J. Vugts ; Guus A.M.S. van Dongen ; Wiesje M. van der Flier ; Mario Ries ; Dannis G. van Vuurden ; Everard G.B. Vijverberg ; Elsmarieke van de Giessen (2025): Drug delivery strategies to cross the blood-brain barrier in Alzheimer’s disease: a comprehensive review on three promising strategies. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100204
DOSE- AND PATTERN- PHYSICAL ACTIVITY IS ASSOCIATED WITH LOWER RISK OF DEMENTIA
Yan Wang, Fangyu Li, Shuman Cao, Jianping Jia
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: The amount and pattern of physical activity that benefits cognitive health remain unclear.
METHODS: Participants from the UK Biobank cohort who had a full week of accelerometer-based moderate-to-vigorous physical activity (MVPA) and light physical activity (LPA) data were included in the analysis. The data for dementia diagnosis were collected from 2006 to 2024. Associations between the incidence of all-cause dementia, Alzheimer’s disease (AD), vascular dementia (VaD), and PA amounts and patterns were assessed using Cox proportional hazards regression models. The analysis included 1) comparing MVPA gradients with reference group performing less than 150 min/week; 2) classifying MVPA patterns as effective intensive (≥300 min/week with ≥50 % of MVPA in 1–2 days), effective regular (≥300 min/week not up to effective intensive), and ineffective (<300 min/week); 3) performing stratified analyses by age, sex, and APOE ε4 carrier status; and 4) evaluating the association between LPA and dementia risk among participants classified as ineffective MVPA levels.
RESULTS: 91,512 individuals (mean [SD] age, 56.03[7.8] years; 55.9 % female) were included. Compared with participants performing <150 min of MVPA per week, those accumulating 150–299 min/week, whether through concentrated (1–2 days) or regular pattern, did not show significantly lower dementia incidence. However, accumulating >300 min/week of MVPA was associated with a reduced risk. When stratified at 300 min/week of MVPA, hazard ratios for dementia were 0.73 (95 % CI: 0.60–0.89) for the weekend pattern and 0.79 (95 % CI: 0.64–0.98) for the regular pattern. For ineffective MVPA, engaging in >840 min/week of LPA was associated with lower dementia incidence.
CONCLUSIONS: Accumulating >300 min/week of MVPA, whether concentrated within 1–2 days or distributed evenly across the week, was associated with a decreased risk of dementia. Additionally, higher levels of LPA partially compensated for low MVPA in lowering dementia risk.
CITATION:
Yan Wang ; Fangyu Li ; Shuman Cao ; Jianping Jia (2025): Dose- and pattern- physical activity is associated with lower risk of dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100223
LIFETIME WALKING AND ALZHEIMER’S PATHOLOGY: A LONGITUDINAL STUDY IN OLDER ADULTS
Jee Wook Kim, Musung Keum, Min Soo Byun, Dahyun Yi, So Yeon Jeon, Joon Hyung Jung, Nayeong Kong, Yoon Young Chang, Gijung Jung, Hyejin Ahn, Jun-Young Lee, Koung Mi Kang, Chul-Ho Sohn, Yun-Sang Lee, Yu Kyeong Kim, Dong Young Lee, KBASE Research Group
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryIMPORTANCE: While many studies have shown that greater amounts or longer durations of walking are associated with a lower risk of Alzheimer’s disease (AD) or cognitive decline in older adults, the neuropathological basis for this is not yet fully understood.
OBJECTIVE: To examine the relationship between walking intensity and duration and longitudinal changes in Alzheimer’s disease (AD)-related brain pathologies, including Aβ and tau accumulation, neurodegeneration, and white matter hyperintensity (WMH).
DESIGN: Data were drawn from the Korean Brain Aging Study for the Early Diagnosis and Prediction of AD, a longitudinal cohort study (initiated in 2014).
SETTING: Community and memory clinic setting.
PARTICIPANTS: One hundred fifty-one older adults.
MAIN OUTCOME AND MEASURES: Participants underwent baseline and 4-year follow-up neuroimaging assessments. Lifetime walking, as measured using the Lifetime Total Physical Activity Questionnaire, was categorized by intensity (high vs. low) and duration (short ≤360 min/week vs. long >360 min/week), forming four combined walking groups. Aβ and tau deposition, neurodegeneration, and WMH volume were assessed via PET/MRI.
RESULTS: Long-duration or high-intensity walking was associated with significantly reduced Aβ accumulation over 4 years. The high-combined walking group showed similar benefits, while medium-combined groups did not. The effect was significant only in the early life-initiated walking subgroup. No associations were found with tau, neurodegeneration, or WMH volume.
CONCLUSIONS: Long-duration, high-intensity walking may reduce brain Aβ accumulation, potentially lowering AD risk, particularly when initiated before late life.
CITATION:
Jee Wook Kim ; Musung Keum ; Min Soo Byun ; Dahyun Yi ; So Yeon Jeon ; Joon Hyung Jung ; Nayeong Kong ; Yoon Young Chang ; Gijung Jung ; Hyejin Ahn ; Jun-Young Lee ; Koung Mi Kang ; Chul-Ho Sohn ; Yun-Sang Lee ; Yu Kyeong Kim ; Dong Young Lee ; ; , KBASE Research Group m ; Show more ; (2025): Lifetime walking and Alzheimer’s pathology: A longitudinal study in older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100203
SERUM BDNF AND PROGRESSION TO MCI IN COGNITIVELY NORMAL OLDER ADULTS: A PROSPECTIVE COHORT STUDY
Kyungtae Kim, Min Soo Byun, Dahyun Yi, Joon Hyung Jung, Bo Kyung Sohn, Gijung Jung, Hyejin Ahn, Jun-Young Lee, Yun-Sang Lee, Yu Kyeong Kim, Kwangsik Nho, Dong Young Lee, for the KBASE Research Group
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the mammalian brain. Preclinical studies suggest that BDNF influences the pathophysiology of Alzheimer's disease. In humans, higher blood BDNF levels have been associated with a lower risk of dementia. However, the relationship between serum BDNF levels and the progression to mild cognitive impairment (MCI) in cognitively normal (CN) individuals remains uncertain.
OBJECTIVES: To examine whether higher serum BDNF levels in CN older adults are associated with a reduced incidence of MCI over a 4-year follow-up period and to identify potential moderators of this relationship.
DESIGN: Longitudinal analyses were conducted using follow-up data from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease, an ongoing prospective cohort study. Data were collected from January 1, 2014, to May 31, 2021, and analyzed from May 1, 2023, to September 30, 2023.
SETTING: Community and memory clinic setting.
PARTICIPANTS: A total of 274 CN older adults aged 55–90 years were included at baseline.
MEASUREMENT: Progression to MCI over the 4-year follow-up period.
RESULTS: Among the 274 participants, 26 developed MCI during follow-up. The high BDNF group had a significantly lower incidence of MCI compared to the low BDNF group (hazard ratio [HR], 0.27; 95 % confidence interval [CI], 0.11–0.69; P = 0.006). This association persisted even after adjusting for BDNF Val66Met polymorphism, amyloid PET positivity, vascular risk factors, cholesterol levels, triglycerides, homocysteine, BMI, smoking, alcohol, TBI history, CES-D, and MMSE scores (HR, 0.14; 95 % CI, 0.05–0.40; P < 0.001). Subgroup analyses further revealed that the association was significant only in women (HR, 0.12; 95 % CI, 0.03–0.48; P = 0.002), individuals aged <75 years (HR, 0.16; 95 % CI, 0.03–0.77; P = 0.022), those with less than a college degree (HR, 0.23; 95 % CI, 0.07–0.74; P = 0.013), and amyloid PET-negative (HR, 0.29; 95 % CI, 0.11–0.72; P = 0.014) individuals.
CONCLUSIONS: These findings suggest a protective role of BDNF against clinical progression to MCI in cognitively healthy older individuals. This effect appears to be more prominent in women, as well as in relatively younger, less educated, and amyloid PET-negative individuals.
CITATION:
Kyungtae Kim ; Min Soo Byun ; Dahyun Yi ; Joon Hyung Jung ; Bo Kyung Sohn ; Gijung Jung ; Hyejin Ahn ; Jun-Young Lee ; Yun-Sang Lee ; Yu Kyeong Kim ; Kwangsik Nho ; Dong Young Lee ; for the KBASE Research Group (2025): Serum BDNF and progression to MCI in cognitively normal older adults: A prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100210
ADVANCING THE SCIENCE OF RECRUITMENT FOR ALZHEIMER’S CLINICAL TRIALS: CHALLENGES AND OPPORTUNITIES
Paul Aisen, Desi Peneva, Maria-Alice Manetas, Mireille Jacobson, Dana Goldman, Niranjan Bose, Phyllis Barkman Ferrell, VK Vu, Rema Raman
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryDespite recent advancements in Alzheimer’s disease therapeutics and diagnostics, significant challenges remain in accelerating participant recruitment—particularly among diverse populations—and ensuring equitable access to clinical trials. This paper summarizes discussions and recommendations from the 2024 Roundtable on Advancing the Science of Recruitment for Inclusive Alzheimer’s Disease Clinical Trials, hosted by the USC Clinical Trial Recruitment Lab (CTRL). Bringing together 40 leading experts from across the Alzheimer’s clinical trial ecosystem in the U.S., including thought leaders from academia, industry, government and philanthropy, the Roundtable examined critical barriers to inclusivity and explored emerging recruitment approaches. Discussions highlighted the need for strategies that expand patient access, remove systemic barriers, and foster inclusivity in clinical research.
CITATION:
Paul Aisen ; Desi Peneva ; Maria-Alice Manetas ; Mireille Jacobson ; Dana Goldman ; Niranjan Bose ; Phyllis Barkman Ferrell ; VK Vu, ; Rema Raman (2025): Advancing the science of recruitment for Alzheimer’s clinical trials: Challenges and opportunities. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100230
PLASMA P-TAU217 PREDICTING BRAIN-WIDE TAU ACCUMULATION IN PRECLINICAL AD
Hasom Moon, Xi Chen, Alzheimer’s Disease Neuroimaging Initiative
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: Recently developed blood test of Alzheimer’s disease (AD) has been recognized as a promising alternative to CSF and PET, as it is noninvasive, cost-effective, and more accessible. Particularly, plasma p-tau217 shows high sensitivity in detecting β-amyloid (Aβ) and tau positivity in early AD. However, the potential value of p-tau217 in revealing Aβ and tau distribution and predicting future development has not been studied.
OBJECTIVES: We investigated the dose-response associations between p-tau217 and regional Aβ and tau measured by PET, as well as the longitudinal prediction of p-tau217 for prospective Aβ and tau accumulation measured by longitudinal PET.
DESIGN: Cross-sectional and longitudinal analyses.
SETTING: We used data in Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) study (N = 333) for primary analyses and Alzheimer’s Disease Neuroimaging Initiative (ADNI) (N = 410) for validation.
PARTICIPANTS: Cognitively unimpaired older adults (N = 333) from A4 study and cognitively unimpaired older adults (N = 222), mild cognitive impairment (N = 114), and dementia (N = 74) from ADNI.
MEASUREMENTS: Plasma p-tau217 was measured using Lilly (A4) and Fujirebio (ADNI) assays. 18-FFlorbetapir PET and 18-FFlortaucipir PET measured regional Aβ and tau.
RESULTS: Plasma p-tau217 was associated with concurrent Aβ in most cortical regions and tau in temporo-parietal cortices. Longitudinally, p-tau217 predicted brain-wide tau accumulation in widespread cortical regions in preclinical AD, but not Aβ change anywhere.
CONCLUSIONS: Plasma p-tau217 shows dose-response, brain-wide relationships with concurrent Aβ and future tau development in preclinical AD, suggesting its potential in disease trajectory monitoring and large-scale screening for individuals approaching certain biological stages of AD in clinical trials.
CITATION:
Hasom Moon ; Xi Chen ; Alzheimer’s Disease Neuroimaging Initiative (2025): Plasma p-tau217 predicting brain-wide tau accumulation in preclinical AD. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100252
LOWER BASELINE AMYLOID BETA BURDEN IS ASSOCIATED WITH GREATER PERCENT OF AMYLOID BETA POSITRON EMISSION TOMOGRAPHY REDUCTION AND BETTER CLINICAL OUTCOMES IN THE ADUCANUMAB PHASE 3 TRIALS ENGAGE AND EMERGE IN EARLY ALZHEIMER\'S DISEASE
Jackson Burton, Holly M. Brothers, R. Matthew Hutchison, Jennifer Murphy, Tao Sun, Gersham Dent, Gioacchino Curiale, Ken Kowalski
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: Aducanumab is a human immunoglobulin G1 anti-amyloid beta antibody for early-stage Alzheimer’s disease. After the discontinuation of the aducanumab clinical program and market withdrawal, the Phase 3 data were further assessed to characterize the relationship between baseline amyloid beta load, degree of amyloid beta removal, and subsequent clinical outcomes to provide context for future research.
OBJECTIVES: This analysis leveraged modelling techniques to impute missing amyloid beta positron emission tomography values and better understand the relationship between baseline amyloid beta positron emission tomography status, amyloid beta positron emission tomography reduction, and clinical outcomes in the aducanumab Phase 3 ENGAGE and EMERGE (NCT02477800/NCT02484547) studies.
DESIGN: Exploratory data analysis.
SETTING: A previously developed model which characterized the relationship between aducanumab exposure and amyloid beta positron emission tomography standard uptake value ratio was updated to impute centiloid values for participants not enrolled in the amyloid beta positron emission tomography substudy. Additional clinically-relevant variables were also summarized.
PARTICIPANTS: 1876 participants with baseline amyloid beta positron emission tomography and clinical endpoints in a pooled ENGAGE/EMERGE dataset at week 78.
INTERVENTION: Aducanumab.
MEASUREMENTS: Amyloid burden measured by centiloids and clinical endpoints.
RESULTS: In older participants whose baseline amyloid beta burden is lower than the average trial population, exposure to aducanumab provides greater clinical benefit across cognitive and functional endpoints.
CONCLUSIONS: The relationship between baseline amyloid beta load and treatment benefit in a large population after exposure to an amyloid beta–directed antibody provides insight into which subpopulations are likely to benefit from this class of treatment.
CITATION:
Jackson Burton ; Holly M. Brothers ; R. Matthew Hutchison ; Jennifer Murphy ; Tao Sun ; Gersham Dent ; Gioacchino Curiale ; Ken Kowalski (2025): Lower baseline amyloid beta burden is associated with greater percent of amyloid beta positron emission tomography reduction and better clinical outcomes in the aducanumab Phase 3 trials ENGAGE and EMERGE in early Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100202
ESTIMATION OF THE VALUE-BASED PRICE OF A BLOOD TEST FOR ALZHEIMER’S DISEASE PATHOLOGY IN PRIMARY AND SPECIALTY CARE IN THE U.S.
Soeren Mattke, Jiahe Chen, Mark Hanson, Kim G. Johnson, Cara Leahy, David A. Merrill, Victoria Shada, Jorge G. Ruiz
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: Blood tests for the pathology of Alzheimer’s disease (AD) are emerging as alternative to amyloid PET scans and analysis of cerebrospinal fluid. (CSF). However, their economic value, which depends on test accuracy as well as effect on clinical decision-making, remains unclear.
METHODS: We use a Markov model to estimate the value-based price of a blood test with sensitivity of 88 % and specificity of 89 %, if labeled for triage and confirmation of the AD pathology in primary and specialty care. The value-based price was defined as price of the test, at which overall diagnostic cost per true positive case of early-stage AD would equate that under standard of care (identification in primary care and referral to specialty care based on the results of a brief cognitive test). Assumptions for the effect of test use on clinical decisions came from a structured expert consultation process.
RESULTS: If used in primary care, the value-based price would be $290 for a triage and $1150 for a confirmatory test, respectively, as use of PET or CSF testing would decline by 47 % and 86 %, respectively. If used in specialty care, i.e., after confirmation of early-stage cognitive impairment, the overall number of blood tests would decline. Consequently, the value-based price would increase to $450 for a triage test and $1950 for a confirmatory test.
CONCLUSION: The results project substantial cost savings from implementing a blood test for AD pathology within the diagnostic pathway based on modeling results, which future research should confirm with actual data.
CITATION:
Soeren Mattke ; Jiahe Chen ; Mark Hanson ; Kim G. Johnson ; Cara Leahy ; David A. Merrill ; Victoria Shada ; Jorge G. Ruiz (2025): Estimation of the value-based price of a blood test for Alzheimer’s disease pathology in primary and specialty care in the U.S.. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100219
USING MACHINE LEARNING AND ELECTRONIC HEALTH RECORD (EHR) DATA FOR THE EARLY PREDICTION OF ALZHEIMER\'S DISEASE AND RELATED DEMENTIAS
Sonia Akter, Zhandi Liu, Eduardo J. Simoes, Praveen Rao
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: Over 6 million patients in the United States are affected by Alzheimer's Disease and Related Dementias (ADRD). Early detection of ADRD can significantly improve patient outcomes through timely treatment.
OBJECTIVE: To develop and validate machine learning (ML) models for early ADRD diagnosis and prediction using de-identified EHR data from the University of Missouri (MU) Healthcare.
DESIGN: Retrospective case-control study.
SETTING: The study used de-identified EHR data provided by the MU NextGen Biomedical Informatics, modeled with the PCORnet Common Data Model (CDM).
PARTICIPANTS: An initial cohort of 380,269 patients aged 40 or older with at least two healthcare encounters was narrowed to a final dataset of 4,012 ADRD cases and 119,723 controls.
METHODS: Six ML classifier models: Gradient-Boosted Trees (GBT), Light Gradient-Boosting Machine (LightGBM), Random Forest (RF), eXtreme Gradient-Boosting (XGBoost), Logistic Regression (LR), and Adaptive Boosting (AdaBoost) were evaluated using Area Under the Receiver Operating Characteristic Curve (AUC-ROC), accuracy, sensitivity, specificity, and F1 score. SHAP (SHapley Additive exPlanations) analysis was applied to interpret predictions.
RESULTS: The GBT model achieved the best AUC-ROC scores of 0.809–0.833 across 1- to 5-year prediction windows. SHAP analysis identified depressive disorder, age groups 80–90 yrs and 70–80 yrs, heart disease, anxiety, and the novel risk factors of sleep apnea, and headache.
CONCLUSION: This study underscores the potential of ML models for leveraging EHR data to enable early ADRD prediction, supporting timely interventions, and improving patient outcomes. By identifying both established and novel risk factors, these findings offer new opportunities for personalized screening and management strategies, advancing both clinical and informatics science.
CITATION:
Sonia Akter ; Zhandi Liu ; Eduardo J. Simoes ; Praveen Rao (2025): Using machine learning and electronic health record (EHR) data for the early prediction of Alzheimer's Disease and Related Dementias. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100169
COMPARATIVE EFFICACY OF COGNITIVE TRAINING MODALITIES IN COGNITIVE IMPAIRMENT: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS
Li-bing Liang, Shan Wang, Kun-peng Li, Cai-qin Wu
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: Cognitive training is a widely utilized non-pharmacological intervention to enhance cognitive performance in individuals with cognitive impairment. Despite its potential, significant ambiguity remains regarding its definition, optimal modalities, and design parameters. It remains unclear which types of cognitive training are relatively optimal for different levels of cognitive impairment or how intervention designs can maximize therapeutic benefits.
OBJECTIVES: This systematic review and network meta-analysis aimed to compare the effects of various cognitive training modalities on cognitive, psychological, and quality-of-life outcomes in individuals with cognitive impairment. Additionally, it sought to identify optimal intervention approaches, clarify key design parameters, and examine critical factors influencing treatment efficacy.
METHODS: A comprehensive search was conducted across 12 databases from the establishment of the database until October 24, 2024, to identify eligible randomized controlled trials (RCTs) evaluating cognitive training interventions. Data were analyzed using pairwise meta-analysis and network meta-analysis in Review Manager 5.4 and Stata 18.
RESULTS: Totally 43 RCTs were included. Pairwise meta-analysis revealed that cognitive strategy training demonstrated superior to active control (AC) or passive control (PC) in improving language function, immediate memory, depressive symptoms and quality of life. However, no significant effects were detected regarding cognitive impairment severity, delivery format, interventionist expertise level, training duration, or control type. Network meta-analysis further identified reminiscence therapy as the most pronounced effective intervention for improving global cognition across all stages of cognitive impairment.
CONCLUSIONS: Reminiscence therapy has been demonstrated as a relatively optimal cognitive training modality for enhancing cognitive function in individuals with varying levels of cognitive impairment. Future studies should prioritize longitudinal investigations to validate the durability of therapeutic benefits and incorporate neuroimaging and biomarker analyses to elucidate underlying mechanisms. High-quality RCTs remain imperative to strengthen the evidence base and evaluate the consistency of effects across diverse cognitive training interventions.
CITATION:
Li-bing Liang ; Shan Wang ; Kun-peng Li ; Cai-qin Wu (2025): Comparative efficacy of cognitive training modalities in cognitive impairment: A systematic review and network meta-analysis. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100207
THE PATIENT PATHWAY FOR MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER’S DISEASE IN ASIA: CURRENT PRACTICES, BARRIERS, AND EXPERT RECOMMENDATIONS FOR OPTIMIZATION
Seong Hye Choi, SangYun Kim, Paulus Anam Ong, Ai Vyrn Chin, Jacqueline Dominguez, Jacqueline Dominguez, Vorapun Senanarong, Chaur-Jong Hu, Manjari Tripathi, Vincent Mok, Gandan Jiang, Amitabh Dash
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: The age-standardized prevalence of Alzheimer’s disease in Asia has increased rapidly in recent years. Disease-modifying treatments that can slow disease progression are now becoming available for patients with early-stage Alzheimer’s disease, including those with mild cognitive impairment. However, challenges in diagnosis and assessment for these patients remain.
OBJECTIVES: This study characterized the care pathway for mild cognitive impairment due to Alzheimer’s disease in Asia, including barriers to care, and considered the future treatment landscape, with the aim of making recommendations for optimizing the care pathway in readiness for the availability of new disease-modifying treatments.
DESIGN: Qualitative study based on semi-structured interviews.
SETTING: Interviews were conducted with physicians in general/tertiary hospitals in Hong Kong, India, Indonesia, Korea, Malaysia, the Philippines, Singapore, Taiwan, and Thailand. Physicians from mainland China and Japan were not included.
PARTICIPANTS: Physicians managing patients with mild cognitive impairment.
MEASUREMENTS: Number and/or proportion of participants providing a given response, and numerical estimates provided by interview participants.
RESULTS: Forty-four physicians, primarily neurologists (n = 31; 70.5 %), were interviewed. Participants managed a median of 67.5 patients with mild cognitive impairment per month, of whom 24.0–87.5 % had mild cognitive impairment due to Alzheimer’s disease. Clinical investigations routinely comprised brief neuropsychological assessments, such as the Mini-Mental State Examination (n = 41), as well as neurological tests (n = 39) and magnetic resonance imaging (n = 40). Except in Korea, comprehensive neuropsychological test batteries and amyloid positron emission tomography were seldom conducted in Asia. Most patients with mild cognitive impairment due to Alzheimer’s disease were treated with nootropics and/or acetylcholinesterase inhibitors (Korea, 96 %; all other regions, 69 %), and almost all were recommended a non-pharmacological treatment (Korea, 93 %; all other regions, 100 %). Detection of mild cognitive impairment due to Alzheimer’s disease was considered prompt in Korea but suboptimal in other regions (n = 16) owing to low disease awareness among patients. Barriers to assessment and diagnosis included delayed healthcare visits for initial assessment (n = 7), neuroimaging backlogs (n = 6), and insufficient neuropsychology resources (n = 13). Access to amyloid biomarker tests, including amyloid positron emission tomography, cerebrospinal fluid analysis, and blood tests, was limited in regions other than Korea.
CONCLUSIONS: The survey findings showed that screening and diagnostic processes for mild cognitive impairment due to Alzheimer’s disease in Asia require further optimization. Efforts should also be made to educate patients and caregivers, improve the diagnostic capabilities of primary and secondary healthcare providers, and reinforce cognitive screening services. The provision and reimbursement of confirmatory tests of amyloid burden should be expanded across the region to facilitate access to innovative disease-modifying therapies.
CITATION:
Seong Hye Choi ; SangYun Kim ; Paulus Anam Ong ; Ai Vyrn Chin ; Jacqueline Dominguez ; Christopher Li-Hsian Chen ; Vorapun Senanarong ; Chaur-Jong Hu ; Manjari Tripathi ; Vincent Mok ; Gandan Jiang ; Amitabh Dash (2025): The patient pathway for mild cognitive impairment due to Alzheimer’s disease in Asia: Current practices, barriers, and expert recommendations for optimization. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100215
SALIVARY LEVELS OF AMYLOID BETA REFLECT BRAIN AMYLOID BETA BURDEN IN COGNITIVELY-NORMAL OLDER ADULTS
Alison R. Bamford, Jenna N. Adams, Soyun Kim, Lisa M. Taylor, Nandita Tuteja, Liv C. McMillan, Negin Sattari, Ivy Y. Chen, Miranda G. Chappel-Farley, Yuritza Escalante, Alyssa L. Lawrence, Novelle J. Meza, Destiny E. Berisha, Abhishek Dave, Rond Malhas, Mark Mapstone, Bryce A. Mander, Michael A. Yassa, Elizabeth A. Thomas
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: Amyloid beta (Aβ) plaque burden, as measured by positron emission tomography (PET), is increasingly being used as a biomarker for Alzheimer's disease (AD) as well as a screening or monitoring tool for clinical trials with amyloid-lowering drugs. However, PET imaging is expensive, invasive and not widely available for all patients, necessitating alternative means to assess brain Aβ accumulation.
OBJECTIVES: In this study, we measured levels of Aβ42, Aβ40 and Aβ38 in saliva samples from cognitively unimpaired older adults (n=93; 61.7 % female; mean age = 70.1 ± 6.6 years) using the Mesoscale Discovery platform, carefully considering preanalytical variables, including timing of sample collection, blood contamination and sample concentration. We next determined the relationships between Aβ peptide levels and Aβ plaque burden within the brain, determined using 18F-florbetapir (FBP) PET.
RESULTS: We found that salivary levels of Aβ38 and Aβ42, but not Aβ40 nor the Aβ42/Aβ40, were significantly positively correlated with the global mean FBP standardized uptake value ratio (SUVR), before and after adjusting for age, sex and time of day of saliva sample collection (r=0.523/0.544, p=0.001/0.002 and r=0.316/0.32, p=0.031/0.044, for Aβ38 and Aβ42, respectively). Similar results were observed when Aβ values were analyzed as a ratio to the total protein levels in each sample and when tested in saliva samples that were collected during a restricted morning time window. Using composite regions which represent cortical regions vulnerable to Aβ accumulation in early, intermediate, and late stages of AD, we found that Aβ38 showed the most robust correlation with FBP SUVRs from early-accumulating brain regions (r=0.510; p<0.001). In contrast to the observed effects in saliva, plasma levels of Aβ42 measured from a subset of the participants showed a significant negative correlation to mean FBP SUVR. Using logistic regression analysis to determine whether any salivary Aβ species could predict brain Aβ burden, we found that salivary levels of Aβ38 in combination with age, sex, sample timing and APOE genotype could predict Aβ-PET positivity with an area under the curve = 0.950 (95 % confidence interval, 0.876–1.0; p<0.0001).
CONCLUSIONS: Our findings suggest that salivary Aβ38 and/or Aβ42 could have relevance as a non-invasive, and more widely applicable biomarker, for utility in clinical studies on AD.
CITATION:
Alison R. Bamford ; Jenna N. Adams ; Soyun Kim ; Lisa M. Taylor ; Nandita Tuteja ; Liv C. McMillan ; Negin Sattari ; Ivy Y. Chen ; Miranda G. Chappel-Farley ; Yuritza Escalante ; Alyssa L. Lawrence ; Novelle J. Meza ; Destiny E. Berisha ; Abhishek Dave ; Rond Malhas ; Mark Mapstone ; Bryce A. Mander ; Michael A. Yassa ; Elizabeth A. Thomas ; (2025): Salivary levels of amyloid beta reflect brain amyloid beta burden in cognitively-normal older adults. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100216
ASSOCIATION OF MULTIMORBIDITY AND DISEASE CLUSTERS WITH NEUROIMAGING AND COGNITIVE OUTCOMES IN UK BIOBANK
Shehab Uddin Al Abid, Catherine M Calvin, Danial Qureshi, Michele Veldsman, El?bieta Ku?ma, Thomas J. Littlejohns
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: The relationship between multimorbidity, particularly disease clusters, with neuroimaging and cognitive outcomes that typically manifest prior to clinical diagnosis of dementia, remains understudied. This study investigated whether multimorbidity is associated with dementia-related neuroimaging and cognitive outcomes in the UK Biobank cohort.
METHODS: This cross-sectional study used data from UK Biobank participants who attended imaging assessments between 2014–2023, and were free from neurological conditions, including dementia. Multimorbidity was defined as the coexistence of two or more long-term conditions, selected from a standardised criteria of 39 conditions. Latent class analyses were used to identify disease clusters. Neuroimaging outcomes were measured using magnetic resonance imaging, and cognition was assessed by seven tests measuring different cognitive domains. Multivariable linear regression was used to assess the association between multimorbidity and disease clusters with neuroimaging and cognitive outcomes.
RESULTS: A total of 43,160 participants were included (mean [standard deviation] age, 64.2 [7.7] years, 53.1 % female). Multimorbidity was present among 14,339 (33.2 %) participants, and was associated with reduced grey matter volume, total brain volume, left hippocampal volume, increased cerebrovascular pathology as well as reduced domain-specific cognitive function. A strong dose-response relationship was observed with the increasing number of multimorbid conditions across these outcomes. A disease cluster driven by cardiometabolic conditions was consistently associated with poorer brain health across all outcomes. Disease clusters driven by respiratory, mental health and other conditions showed less consistent associations.
CONCLUSIONS: Multimorbidity was strongly associated with poorer brain health, particularly within the cardiometabolic disease cluster. Given that UK Biobank participants are, on average, healthier than the general population, future studies in more diverse and representative cohorts would be valuable.
CITATION:
Shehab Uddin Al Abid ; Catherine M Calvin ; Danial Qureshi ; Michele Veldsman ; Elżbieta Kuźma ; Thomas J. Littlejohns (2025): Association of multimorbidity and disease clusters with neuroimaging and cognitive outcomes in UK Biobank. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100208
A SIX-YEAR RISK ASSESSMENT FOR DEMENTIA AND ALZHEIMER\'S DISEASE IN THE GENERAL POPULATION THROUGH IMMUNOPRECIPITATION-MASS SPECTROMETRY PLASMA AMYLOID QUANTIFICATION
Germain U. Busto, Christophe Hirtz, Isabelle Carriere, Karim Bennys, Laure-Anne Gutierrez, Jana Kindermans, Catherine Helmer, Audrey Gabelle, Sylvain Lehmann, Claudine Berr
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: Identifying individuals at risk for dementia and Alzheimer’s disease (AD) in the general population (GP) is increasingly essential due to new diagnostic criteria and opportunities for effective interventions. Plasma-based biomarkers (pBB) offer a promising approach for detecting positive amyloid profile. However, their effectiveness in predicting clinical dementia and AD risk at the GP level remains largely unexplored.
OBJECTIVES: To assess the risk of clinical dementia and AD using pBB amyloid biomarkers in GP using the most up-to-date proteomic techniques.
DESIGN: Case-cohort study randomly selected from a prospective cohort.
SETTING: The three-city community-living study.
PARTICIPANTS: Over 65 years recruited from the electoral rolls of three French cities.
MEASUREMENTS: pBB amyloid levels (Aβ42, Aβ40 and APP669–711) were measured in the plasma using the mass spectrometry-based (IPMS)-Shimadzu modified technology. Patients were monitored for up to 6 years for incident dementia and AD according to DSM-IV and NINCDS/ADRDA criteria. Cox proportional hazard models adjusted for multiple covariables, including age and renal function, were used to estimate hazard ratios.
RESULTS: Plasma samples from 327 participants were analyzed with a mean age 83 years (80–87), 64.8 % females and a median follow-up time of 2.7 years (0.8–4.8) and including 121 incident dementia cases. Our findings indicate that the Aβ42/Aβ40 ratio, along with a composite score that encompasses APP669–711 and Aβ40/Aβ42 ratios, serves as significant predictors of clinical dementia [HR(95 %CI) = 3.52 (1.69–7.32), p-value<0.001 and 4.34 (2.06–9.17), p-value<0.001, respectively] and AD risk over a six-year period, while also accounting for age and sex interactions. Furthermore, elevated Aβ40 levels correlate with an increased risk of developing dementia (HR=2.56, 95 % CI 1.22–5.35, p = 0.01) and AD (HR=2.60, 95 %CI 1.06–6.36, p = 0.04), and our study confirms that Aβ42 concentrations are significantly influenced by renal function.
CONCLUSIONS: This research advances the potential application of plasma amyloid biomarkers for assessing the risk of clinical dementia and AD in the general population within short period of time, positioning it as a valuable tool alongside existing plasma PT217 biomarkers or using ratio of both of them.
CITATION:
Germain U. Busto ; Christophe Hirtz ; Isabelle Carriere ; Karim Bennys ; Laure-Anne Gutierrez ; Jana Kindermans ; Catherine Helmer ; Audrey Gabelle ; Sylvain Lehmann ; Claudine Berr (2025): A six-year risk assessment for dementia and Alzheimer's disease in the general population through immunoprecipitation-mass spectrometry plasma amyloid quantification. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100186
BRAIN PHOTOBIOMODULATION: A POTENTIAL TREATMENT IN ALZHEIMER’S AND PARKINSON’S DISEASES
Guillaume Blivet, Benjamin Touchon, Hugo Cavadore, Sara Guillemin, Frédéric Pain, Michael Weiner, Marwan Sabbagh, Cécile Moro, Jacques Touchon
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryAlzheimer’s Disease (AD) and Parkinson’s Disease (PD) are common neurodegenerative diseases, characterized by the progressive loss of synapses and neurons, leading to cognitive and motor decline. Their pathophysiology includes cerebral lesions, oxidative stress, neuroinflammation as well as brain-gut axis microbiota dysbiosis.
Preclinical investigations demonstrated that brain photobiomodulation (bPBM) reduces oxidative stress and inflammation, increases cerebral blood flow and enhance neurogenesis and synaptogenesis, which makes bPBM a promising treatment in AD and PD.
This review focuses on the clinical application of bPBM in AD and PD. It aims to provide a scientific overview of the current clinical knowledge, review recent clinical studies findings, and describe future directions and upcoming clinical studies.
So far, several clinical studies investigated bPBM therapy, at various parameters, both in patients with AD and related dementia, and PD. All demonstrate bPBM safety and bring valuable clinical information regarding efficacy, with particularly promising results in AD. However, their exploratory design and inconsistent quality lead to a low level of evidence, which currently does not support the widespread use of bPBM in clinical practice.
Future clinical research should address two gaps: the need for robust double-blinded RCTs vs sham with a higher number of patients and a longer follow-up, and the need for research focusing on dosimetry to determine which bPBM parameters are optimal. The ongoing or unpublished clinical studies on bPBM should fill in this gap.
CITATION:
Guillaume Blivet ; Benjamin Touchon ; Hugo Cavadore ; Sara Guillemin ; Frédéric Pain ; Michael Weiner ; Marwan Sabbagh ; Cécile Moro ; Jacques Touchon (2025): Brain photobiomodulation: a potential treatment in Alzheimer’s and Parkinson’s diseases. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100185
VALUE OF BLOOD NEURAL CELL-DERIVED SMALL EXTRACELLULAR VESICLES IN THE DIAGNOSIS AND PREDICTION OF ALZHEIMER\'S DISEASE: A SYSTEMATIC REVIEW
Weibing Pan, Yu Teng, Xiaowan Han, Shaojiao Liu, Xingxue Pang, Lei Wang, Mingjing Zhao
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBlood neural cell-derived small extracellular vesicles (sEVs) can directly reflect changes in brain tissue and are easier to obtain than cerebrospinal fluid. This article systematically reviews the alterations of proteins and miRNAs from neural cell-derived sEVs in patients with Alzheimer's disease (AD), and summarizes the biomarkers with clinical diagnostic and predictive value. PubMed, Web of Science, Embase, and Cochrane Library were searched for studies in blood neural cell-derived sEVs in AD patients up to May 2024. According to the inclusion and exclusion criteria, the literature was screened, the information was extracted and the quality was evaluated. Proteins and miRNAs from neural cell-derived sEVs were classified and summarized, focusing on target molecules with high diagnostic and predictive values for AD. A final 34 articles reporting 5601 participants were included. In cross-sectional studies, Aβ- and Tau-related proteins (Aβ42, Aβ42/40, p-S396-Tau, p-Tau181), p-S312-IRS-1, and cathepsin D were increased, conversely, synaptic proteins (neurogranin, synaptotagmin, synaptophysin, synaptopodin, NMDAR2A) and REST were decreased in blood neuron-derived sEVs (NDsEVs) of patients with AD. While miR-29c-3p was increased in blood NDsEVs and glial cell-derived sEVs. Each of these proteins and miRNAs demonstrated high AD diagnostic value. Additionally, blood astrocyte-derived sEVs (ADsEVs) showed increased complement effector proteins and decreased complement regulatory proteins with a moderate diagnostic value. In longitudinal cohort studies, three composite models displayed high predictive efficacy for early AD prediction, and could predict the occurrence of AD within 1–10 years. Therefore, Aβ- and Tau-related proteins, synaptic proteins, and miRNA in blood neural cell-derived sEVs demonstrate high AD diagnostic and predictive values serving as important biomarkers. Especially, synaptic proteins showed significant changes in the early clinical stage, which has early predictive value.
CITATION:
Weibing Pan ; Yu Teng ; Xiaowan Han ; Shaojiao Liu ; Xingxue Pang ; Lei Wang ; Mingjing Zhao (2025): Reply to the Letter to the Editor: HeValue of blood neural cell-derived small extracellular vesicles in the diagnosis and prediction of Alzheimer's disease: A systematic reviewaring loss, diet, and cognitive decline: Interconnections for dementia prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100193
ASSOCIATION OF THE DIFFERENCE BETWEEN CYSTATIN C- AND CREATININE-BASED ESTIMATED GLOMERULAR FILTRATION RATE WITH CEREBRAL SMALL VESSEL DISEASE: A LARGE PROSPECTIVE COHORT STUDY
Zhiming Li, Fei Wang, Jincheng Liu, Benbo Xiong, Han Wang, Zijie Wang, Xiao Hu, Qi Li
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND AND OBJECTIVE: It remains unclear whether the difference between the estimated glomerular filtration rate based on cystatin C and creatinine (eGFRdiff) is associated with cerebral small vessel disease (CSVD). We investigated the correlation of eGFRdiff with SCVD and further evaluated the mediating role of blood pressure.
METHODS: This prospective cohort study included 35,590 neurologically healthy participants at baseline (2006 to 2010) from the UK Biobank. eGFRdiff is divided into two indicators: absolute difference (eGFRabdiff) and ratio (eGFRrediff) based on the calculation between cystatin C and creatinine. CSVD was assessed by calculating white matter hyperintensity volume (WMHV) from T2-FLAIR brain MRI scans (conducted between 2014 and 2021), with values normalized to intracranial volume and log-transformed. Multiple linear regression models and mediation analysis was used to evaluate the associations of eGFRdiff with WMHV.
RESULTS: Participants with negative eGFRabdiff had higher WMHV (β = 0.07, 95 % confidence interval [CL] = 0.04 ∼ 0.10), while participants with positive eGFRabdiff had smaller WMHV (β = -0.05, 95 %CL = -0.09 ∼ -0.02), compared to midrange eGFRabdiff group. Meanwhile, participants with eGFRrediff ≤ 0.7 had higher WMHV compared with participants with eGFRrediff > 0.7 (β = 0.08, 95 %CL = 0.01∼ 0.15) .In addition, hypertension mediated the associations between eGFRdiff and WMHV (12.6 % ∼13.2 %).
CONCLUSION: eGFRdiff was independently associated with WMHV. Our findings suggested that monitoring eGFRdiff has potential benefits in identifying the burden of CSVD in the general population in future.
CITATION:
Zhiming Li ; Fei Wang ; Jincheng Liu ; Benbo Xiong ; Han Wang ; Zijie Wang ; Xiao Hu ; Qi Li (2025): Association of the difference between cystatin C- and creatinine-based estimated glomerular filtration rate with cerebral small vessel disease: A large prospective cohort study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100190
POOR GLYMPHATIC FUNCTION IS ASSOCIATED WITH MILD COGNITIVE IMPAIRMENT AND ITS PROGRESSION TO ALZHEIMER\'S DISEASE: A DTI-ALPS STUDY
Cuiping Bao, Hongbin Luo, Jiao Wang, Xuehuan Liu, Yiming Li, Jun Yang, Chong Chen, Rongrong Yang, Weili Ba, Xinying Lian, Michelle Dunk, Jun Liu, Weili Xu
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: We aimed to explore the association between ALPS index and both risks of MCI from cognitively normal (CN) and incident AD progressed from MCI, as well as potential mediating factors.
METHODS: This study included 519 adults including 253 (48.75 %) CN and 266 (51.25 %) MCI participants from Alzheimer's Disease Neuroimaging Initiative. Glymphatic function (assessed by along the perivascular space [ALPS] index) was measured by diffusion tensor image at baseline. Neurobiomarkers (Aβ and tau from CSF, plasma and PET) and cognitive functions were served as mediators. Data were analyzed using Cox and Laplace regression and mediation analysis.
RESULTS: During follow-up (median 3.6 years, interquartile range [IQR]: 2.0–4.9 years), 30 (11.86 %) participants developed MCI in the CN cohort and 73 (27.4 %) participants progressed to AD in the MCI cohort. The hazard ratios (95 % confidence intervals [CIs]) of the higher ALPS index was 0.605 (0.386–0.948) for MCI and 0.501 (0.356–0.706) for AD. In addition, participants with high ALPS index had 3.837 and 3.466 years prolonged onset of MCI and AD, separately. Aβ in choroid plexus (17.1 %), tau in cortex [Inferiortemporal (21.1 %), Middletemporal (AV1451:17.0 %, FTP:15.5 %), Superiortemporal(7.7 %), Meta_temporal (AV1451:17.5 %, FTP:16.6 %)], and executive function (14.1 %) mediated the association between ALPS and MCI-AD progression.
CONCLUSION: High ALPS index decreases MCI risk and delays MCI progression to AD by approximately 3.5 years. Aβ in choroid plexus, tau in cortex, and executive function may partially mediate the MCI-AD progression in relation to ALPS index.
CITATION:
Cuiping Bao ; Hongbin Luo ; Jiao Wang ; Xuehuan Liu ; Yiming Li ; Jun Yang ; Chong Chen ; Rongrong Yang ; Weili Ba ; Xinying Lian ; Michelle Dunk ; Jun Liu ; Weili Xu (2025): Poor glymphatic function is associated with mild cognitive impairment and its progression to Alzheimer's disease: A DTI-ALPS study. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100156
PHENOTYPIC ALTERATIONS IN PERIPHERAL BLOOD B LYMPHOCYTES OF PATIENTS WITH ALZHEIMER\'S DISEASE
Meng-Ting Wang, Ye-Ran Wang, Gui-Hua Zeng, Xiao-Qin Zeng, Zhang-Cheng Fei, Jia Chen, Jin Zhou, Xin-Peng Li, Zhi-Qiang Xu, Yan-Jiang Wang, Yu-Hui Liu
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryINTRODUCTION: Dysfunction of humoral immunity has been implicated in the pathogenesis of Alzheimer's disease (AD). The distribution of B lymphocyte subsets and their clinical relevance in AD remain unclear.
OBJECTIVE: In this study, we aimed to investigate the distribution of peripheral blood B lymphocyte subsets and their relevance with cognition and biomarkers in AD.
DESIGN, SETTING, AND PARTICIPANTS: We evaluated the immunophenotype of peripheral B lymphocytes in 27 AD patients confirmed by PET-Amyloid scan and 32 cognitively normal controls.
RESULTS: The phenotype of B lymphocytes is altered in AD patients. AD patients exhibit a decrease in both the numbers and proportions of switched memory (SwM) B cells and double-negative (DN) B cells. The proportion of unswitched memory (USwM) B cells was increased after in vitro stimulation. Additionally, B cells that produce proinflammatory cytokines including GM-CSF, IFN-γ, and TNF-α are increased, while those that produce the anti-inflammatory cytokine IL-10 are decreased in AD patients after in vitro stimulation. These alterations in B cell populations were linked to cognitive functions and biomarkers, including Aβ42/40 and pTau181, in AD patients.
DISCUSSION: This study reveals an altered B-lymphocyte phenotype in AD patients, marked by functional and compositional dysregulation. Further research incorporating mechanistic, longitudinal, and functional studies is needed to determine whether these immune perturbations directly contribute to AD pathogenesis or arise as secondary effects of neurodegeneration.
CITATION:
Meng-Ting Wang ; Ye-Ran Wang ; Gui-Hua Zeng ; Xiao-Qin Zeng ; Zhang-Cheng Fei ; Jia Chen ; Jin Zhou ; Xin-Peng Li ; Zhi-Qiang Xu ; Yan-Jiang Wang ; Yu-Hui Liu (2025): Phenotypic alterations in peripheral blood B Lymphocytes of patients with Alzheimer's Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100135
MULTIMORBIDITY AND RISK OF DEMENTIA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF LONGITUDINAL COHORT STUDIES
Yaguan Zhou, Yating You, Yuting Zhang, Yue Zhang, Changzheng Yuan, Xiaolin Xu
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryBACKGROUND: Chronic diseases (e.g., hypertension, diabetes, and heart diseases) have been proposed as marked predictors of incident dementia. However, synthesised evidence on the effect of multimorbidity on dementia is still lacking. We aim to summarise the association between multimorbidity and risk of dementia in longitudinal cohorts.
METHODS: In this systematic review and meta-analysis, we conducted a systematic search in PubMed, Web of Science and Embase from inception to Dec 14, 2024, to identify longitudinal cohort studies reporting the association between multimorbidity or multimorbidity patterns and risk of dementia. Information of included studies were extracted by three reviewers (YaZ, YY and YuZ), and the quality assessment was conducted using the Newcastle-Ottawa Scale. The inverse-variance weighted random effects meta-analysis was performed to obtain the pooled hazard ratios (HRs) and 95 % confidence intervals (CIs) for dementia associated with multimorbidity and cardiometabolic multimorbidity (CMM). Cochran's Q test and the I2 statistic were used to indicate heterogeneity among the studies. Meta-regression analysis, subgroup analysis and sensitivity analysis were conducted to determine any valid sources of heterogeneity. This study was registered with PROSPERO (CRD42023403684).
RESULTS: We included 17 longitudinal cohort studies (2262,885 middle-aged and older participants) in the systematic review, of which seven were included in meta-analysis. All studies presented moderate to high methodological quality. Meta-analysis showed a positive association between multimorbidity and incident dementia (HR=1.53, 95 % CI=1.12 to 2.09), with substantial heterogeneity (I2=95.2 %). Studies using health records to measure dementia tend to find a stronger positive relationship between multimorbidity and risk of dementia than those using self-report (HRhealth records=1.94, 95 % CI=1.35 to 2.78, I2=94 %; HRself-report=1.17, 95 % CI=1.07 to 1.28, I2=0 %). The impacts of CMM were also observed, and the HRs for dementia ranged from 2.49 (combination of heart diseases and stroke: 95 % CI=1.64 to 3.78) to 3.77 (combination of diabetes, heart diseases and stroke: 95 % CI=2.02 to 7.02). The heterogeneity was moderate, with I2 ranging from 46.9 % (p for heterogeneity=0.152) to 84.1 % (p for heterogeneity=0.002). The impacts of number of diseases, multimorbidity clusters, and multimorbidity trajectory on risk of dementia were narratively summarised due to lacking comparable studies. Limited evidence (only one study) precluded quantitative synthesis for the association of physical and psychological multimorbidity with dementia.
CONCLUSION: Multimorbidity and CMM pattern were significantly associated with risk of dementia, while the effect of physical and psychological multimorbidity remain inconclusive. Individuals affected by multimorbidity should be prioritised in risk factor modification and dementia prevention. Preventing the development of multimorbidity is also crucial—particularly those who already have one chronic disease—in order to maintain cognitive health.
CITATION:
Yaguan Zhou ; Yating You ; Yuting Zhang ; Yue Zhang ; Changzheng Yuan ; Xiaolin Xu (2025): Multimorbidity and risk of dementia: A systematic review and meta-analysis of longitudinal cohort studies. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100164
FINGOLIMOD AMELIORATES AMYLOID DEPOSITION AND NEURODEGENERATION IN APP/PS1 MOUSE MODEL OF ALZHEIMER\'S DISEASE
Meng-Ting Wang, Zi-Cheng Hu, Yang Xiang, Xiao-Qin Zeng, Zhang-Cheng Fei, Jia Chen, Xin-Peng Li, Yu-Peng Zhu, Jun Wang, Yan-Jiang Wang, Zhi-Qiang Xu, Yu-Hui Liu
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryINTRODUCTION: The immune system plays a critical role in regulating amyloid-beta (Aβ) metabolism in Alzheimer's Disease (AD). Both T and B lymphocytes are involved in the pathogenesis of AD. The sphingosine-1-phosphate (S1P) receptor modulator fingolimod used in the treatment of multiple sclerosis, can promote lymphocyte homing, potentially reducing the infiltration of peripheral lymphocytes into the brain.
METHODS: In this study, 8-month-old APP/PS1 mice were orally administered fingolimod at a dose of 1 mg/kg/day or saline as a control for 2 months. After treatment, the mice were subjected to behavioral tests, pathological examinations, and biochemical analyses to evaluate behavioral deficits and AD-type pathologies.
RESULTS: Fingolimod inhibits the infiltration of peripheral lymphocytes into the brain and reduces neuroinflammation. Fingolimod enhances cognitive function and alleviates brain Aβ deposition. Additionally, fingolimod treatment mitigates other AD-related pathologies, including Tau hyperphosphorylation, neuroinflammation, and neurodegeneration. Proteomic analysis further confirms the therapeutic effects of fingolimod in AD, reflected by the downregulation of proteins involved in multiple AD-associated pathways.
DiISCUSSION: This study illustrates that fingolimod effectively ameliorates multiple pathological features of AD, highlighting its potential as a promising therapeutic candidate for the disease.
CITATION:
Meng-Ting Wang ; Zi-Cheng Hu ; Yang Xiang ; Xiao-Qin Zeng ; Zhang-Cheng Fei ; Jia Chen ; Xin-Peng Li ; Yu-Peng Zhu ; Jun Wang ; Yan-Jiang Wang ; Zhi-Qiang Xu ; Yu-Hui Liu (2025): Fingolimod ameliorates amyloid deposition and neurodegeneration in APP/PS1 mouse model of Alzheimer's disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100131
LETTER TO THE EDITOR: COMMENT ON \"HEARING LOSS, DIET, AND COGNITIVE DECLINE: INTERCONNECTIONS FOR DEMENTIA PREVENTION\"
Cuiqing Zhao, Jian Gong, Jia Huang
J Prev Alz Dis 2025;7(12)
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CITATION:
Cuiqing Zhao ; Jian Gong ; Jia Huang (2025): Letter to the Editor: Comment on "Hearing loss, diet, and cognitive decline: interconnections for dementia prevention". The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100189
REPLY TO THE LETTER TO THE EDITOR: HEARING LOSS, DIET, AND COGNITIVE DECLINE: INTERCONNECTIONS FOR DEMENTIA PREVENTION
Xiaoran Liu, Uzma S. Akhtar
J Prev Alz Dis 2025;7(12)
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CITATION:
Xiaoran Liu ; Uzma S. Akhtar (2025): Reply to the Letter to the Editor: Hearing loss, diet, and cognitive decline: Interconnections for dementia prevention. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2025.100188
LETTER TO THE EDITOR: MONITORING OF AMYLOID RELATED IMAGING ABNORMALITIES: SWI VS T2*-GRE
Diana M. Sima, Thanh Vân Phan, Thanh Vân Phan, Wende N. Gibbs, Frederik Barkhof, Philip Scheltens, Stephen Salloway, Jeffrey Cummings, Wim Van Hecke, Dirk Smeets
J Prev Alz Dis 2025;7(12)
Show summaryHide summaryAmyloid-β–directed monoclonal antibody therapies may lead to amyloid-related imaging abnormalities (ARIA). Clinical trials that formed the basis for the ARIA radiographic severity grading scale adopted by the approved drugs’ labels utilized T2* gradient recalled echo (T2*-GRE) images for ARIA-hemorrhagic (ARIA-H) assessment. Little is known about the application of susceptibility-weighted imaging (SWI) to ARIA-H assessment. We exploited comparative studies on the usage of SWI instead of 2D T2*-GRE and simulated the impact of SWI’s higher sensitivity on the derived ARIA-H severity distribution for three approved drugs. The simulations indicated that the two sequences are not equivalent when grading ARIA-H severity and that the rate of therapy discontinuation would increase by more than 50% compared to the rates reported in the drugs’ prescribing information. This should be taken into consideration whenever SWI is applied for ARIA safety monitoring. Appropriate imaging guidelines are needed to enhance management of amyloid-β-directed antibody therapies.
CITATION:
Diana M. Sima ; Thanh Vân Phan ; Ana M. Franceschi ; Wende N. Gibbs ; Frederik Barkhof ; Philip Scheltens ; Stephen Salloway ; Jeffrey Cummings ; Wim Van Hecke ; Dirk Smeets (2025): Letter to the Editor: Monitoring of amyloid related imaging abnormalities: SWI vs T2*-GRE. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100220
ERRATUM TO “INTERCEPT-AD, A PHASE 1 STUDY OF INTRAVENOUS SABIRNETUG IN PARTICIPANTS WITH MILD COGNITIVE IMPAIRMENT OR MILD DEMENTIA DUE TO ALZHEIMER\'S DISEASE”
Eric Siemers, Todd Feaster, Gopalan Sethuraman, Karen Sundell, Vladimir Skljarevski, Erika N. Cline, Hao Zhang, Jasna Jerecic, Lawrence S. Honig, Stephen Salloway, Reisa Sperling, Mirjam N. Trame, Michael G. Dodds, Kimball Johnson
J Prev Alz Dis 2025;7(12)
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CITATION:
Eric Siemers ; Todd Feaster ; Gopalan Sethuraman ; Karen Sundell ; Vladimir Skljarevski ; Erika N. Cline ; Hao Zhang ; Jasna Jerecic ; Lawrence S. Honig ; Stephen Salloway ; Reisa Sperling ; Mirjam N. Trame ; Michael G. Dodds ; Kimball Johnson (2025): Erratum to “INTERCEPT-AD, a phase 1 study of intravenous sabirnetug in participants with mild cognitive impairment or mild dementia due to Alzheimer's disease”. The Journal of Prevention of Alzheimer’s Disease (JPAD).https://doi.org/10.1016/j.tjpad.2025.100213
ERRATUM TO “BIOFLUID BIOMARKER CHANGES FOLLOWING TREATMENT WITH SABIRNETUG (ACU193) IN INTERCEPT-AD, A PHASE 1 TRIAL IN EARLY ALZHEIMER\'S DISEASE”
Erika N. Cline, Daniel Antwi-Berko, Karen Sundell, Elizabeth Johnson, Maddelyn Hyland, Hao Zhang, Hugo Vanderstichele, June Kaplow, Robert A. Dean, Erik Stoops, Eugeen Vanmechelen, Marleen J.A. Koel-Simmelink, Charlotte E. Teunissen, Gopalan Sethuraman, Todd Feaster, Eric Siemers, Jasna Jerecic
J Prev Alz Dis 2025;7(12)
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CITATION:
Erika N. Cline ; Daniel Antwi-Berko ; Karen Sundell ; Elizabeth Johnson ; Maddelyn Hyland ; Hao Zhang ; Hugo Vanderstichele ; June Kaplow ; Robert A. Dean ; Erik Stoops ; Eugeen Vanmechelen ; Marleen J.A. Koel-Simmelink ; Charlotte E. Teunissen ; Gopalan Sethuraman ; Todd Feaster ; Eric Siemers ; Jasna Jerecic (2025): Erratum to “Biofluid biomarker changes following treatment with sabirnetug (ACU193) in INTERCEPT-AD, a phase 1 trial in early Alzheimer's disease”. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100217