The Journal of Prevention of Alzheimer's Disease最新文献

{"title":"Results of the first-in-human, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study of BIIB113 in healthy volunteers.","authors":"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","doi":"10.1016/j.tjpad.2025.100302","DOIUrl":"10.1016/j.tjpad.2025.100302","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objectives: </strong>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.</p><p><strong>Design: </strong>Study 276HV101 was a first-in-human, multicenter, Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose trial.</p><p><strong>Setting: </strong>72 participants were enrolled from February 2022 through July 2023.</p><p><strong>Participants: </strong>Adult healthy female and infertile/vasectomized male participants.</p><p><strong>Intervention: </strong>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.</p><p><strong>Measurements: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>BIIB113 was well tolerated and achieved high levels of target occupancy.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100302"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12413702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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.","authors":"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","doi":"10.1016/j.tjpad.2025.100299","DOIUrl":"10.1016/j.tjpad.2025.100299","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>To investigate the effects of two non-pharmacological interventions on NfL in older adults with SCD.</p><p><strong>Design: </strong>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.</p><p><strong>Setting: </strong>Memory clinics at four sites in France, Germany, Spain, and UK.</p><p><strong>Participants: </strong>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).</p><p><strong>Interventions: </strong>Participants were randomly allocated to the Caring Mindfulness-Based Approach for Seniors (CMBAS) intervention or a structurally matched Health Self-Management Program (HSMP).</p><p><strong>Measurements: </strong>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.</p><p><strong>Results: </strong>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]).</p><p><strong>Conclusions: </strong>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.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: (NCT03005652).</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100299"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12413708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The efficacy and safety of anti-amyloid monoclonal antibody versus acetylcholinesterase inhibitor with an in-depth analysis across genotypes and disease stages: a systematic review and meta-analysis.","authors":"Chih-Wei Hsu, Tien-Wei Hsu, Yu-Chen Kao, Yu-Hsuan Lin, Trevor Thompson, Andre F Carvalho, Brendon Stubbs, Ping-Tao Tseng, Fu-Chi Yang, Chia-Kuang Tsai, Chia-Ling Yu, Yu-Kang Tu, Chih-Sung Liang","doi":"10.1016/j.tjpad.2025.100195","DOIUrl":"10.1016/j.tjpad.2025.100195","url":null,"abstract":"<p><strong>Background: </strong>To date, studies have not compared the efficacy and safety of monoclonal antibodies (mABs) with acetylcholinesterase inhibitors (AChEIs).</p><p><strong>Methods: </strong>Five electronic databases were systemic searched from inception to 10 November 2024 for double-blinded randomized controlled trial (RCT) of patients diagnosed with MCI or mild AD treated with mABs or AChEIs for at least 6 months. The primary outcome was change in cognitive function, measured by the Alzheimer's Disease Assessment Scale-cognitive subscale 14-item (ADAS-Cog) and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SOB). The secondary outcomes were acceptability, tolerability, serious adverse events (SAE), and all -cause mortality. For mABs, amyloid-related imaging abnormalities-edema (ARIA-E), and amyloid-related imaging abnormalities-hemorrhage (ARIA-H) were also assessed. Subgroup analyses included (i) MCI versus mild AD; (ii) with versus without concomitant AD medications; and (iii) Apolipoprotein E (ApoE4) carriers versus non-carriers. Data were pooled using a random effects model within a Bayesian framework.</p><p><strong>Results: </strong>There were 8010 participants (mean age: 71.5 years) across seven mAB trials, and 4993 participants (mean age:70.7 years) in nine AChEI trials. When compared to placebo, only mABs, not AChEIs, were associated with a slower progression of cognitive decline on CDR-SOB (mean difference -0.41 (95 % credible interval -0.61 to -0.22); minimally important difference (MID) -1) and ADAS-Cog (-1.35 (-2.36 to -0.36), MID -2); however, these benefits of mABs did not reach MID across the two cognitive measurements. Besides, mABs were associated with a slower progression of cognitive decline on CDR-SOB (-0.30 (-0.60 to -0.001)) than AChEIs, although mABs and AChEIs did not differ across safety outcomes, including acceptability, tolerability, SAE, and all-cause mortality. Further analysis of mABs indicated that their efficacy did not differ by disease stage, concomitant AD medications, or APOE4 carrier status. However, APOE4 homozygotes carriers were associated with a 5.53-fold (2.48 to 13.07) increased odds of developing ARIA-E compared to non-carriers. Finally, lecanemab demonstrated relatively better efficacy and a more favorable profile on ARIA-E compared to aducanumab and donanemab.</p><p><strong>Conclusions: </strong>mABs were associated with a slower progression of cognitive decline than AChEIs; however, this effect did not reach the MID. The incidence of ARIA-E with mABs was associated with APOE4 carrier status and was not indicative of treatment efficacy.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100195"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12413725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New-generation antidiabetic medications and dementia risk in older adults with type 2 diabetes: A retrospective cohort study.","authors":"Avi Cohen, Stephen Z Levine, Gabriel Vainstein, Michal Schnaider Beeri, Galit Weinstein","doi":"10.1016/j.tjpad.2025.100199","DOIUrl":"10.1016/j.tjpad.2025.100199","url":null,"abstract":"<p><strong>Background: </strong>New-generation antidiabetic medications may have therapeutic potential for dementia, beyond their glycemic effects. However, information from observational studies exploring the association between new-generation antidiabetic use and dementia risk is limited.</p><p><strong>Objectives: </strong>To examine the association between new-generation antidiabetic medication use and dementia risk.</p><p><strong>Design: </strong>Retrospective cohort study using electronic health records of a large non-profit health maintenance organization.</p><p><strong>Participants: </strong>84,798 dementia-free individuals aged ≥65y with type 2 diabetes.</p><p><strong>Measurements: </strong>Antidiabetic medication exposure was based on purchased prescriptions and was used as a time-varying variable. Exposure periods were defined as periods in which either dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), or glucagon-like peptide-1 analogs (GLP-1a) or their combinations were used, otherwise unexposed. Dementia classification was based on the International Classification of Diseases, Ninth Revision codes or antidementia medication prescriptions. Cox regression models were fitted to quantify the association between antidiabetic medication use and incident dementia. Models were adjusted for 13 potential sources of confounding using inverse-probability weighting.</p><p><strong>Results: </strong>Among 84,798 individuals with a mean diabetes onset age of 66.4 ± 7.5 years, the median follow-up for dementia risk was 8.7 years (Q1-Q3: 5.4-12.8). Dementia was diagnosed in 11,642 (13.7%) individuals. New-generation medication use was associated with reduced dementia risk (HR = 0.69; 95% CI, 0.66-0.73) and by drug classes (DPP-4i, HR 0.67 [95% CI 0.63-0.71]; SGLT-2i, 0.63 [95% CI 0.56-0.70], GLP-1a, 0.61 [95% CI 0.54-0.69].</p><p><strong>Conclusions: </strong>The results of this large-scale study suggest that new-generation antidiabetic medication use may be associated with lower dementia risk in older adults with T2D.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100199"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12413712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to Letter to the Editor: \"Refining the evidence linking dietary diversity, genetic susceptibility, and dementia\".","authors":"Boyue Zhao, Feng Zhang","doi":"10.1016/j.tjpad.2025.100246","DOIUrl":"10.1016/j.tjpad.2025.100246","url":null,"abstract":"","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100246"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12413696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Underdetection of neurocognitive disorders in Southern Italy: Evidence from the Salento region.","authors":"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","doi":"10.1016/j.tjpad.2025.100295","DOIUrl":"10.1016/j.tjpad.2025.100295","url":null,"abstract":"<p><strong>Background: </strong>Neurocognitive disorders, including dementia and mild cognitive impairment, are increasingly prevalent, demanding efficient detection and management strategies.</p><p><strong>Objectives: </strong>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.</p><p><strong>Design: </strong>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 %).</p><p><strong>Setting: </strong>Public Centers for Cognitive Disorders and Dementia (CCDDs) across hospital and community services in the Lecce province, Southern Italy.</p><p><strong>Participants: </strong>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).</p><p><strong>Measurements: </strong>Incident cases of neurocognitive disorder, both minor and major, accordingly to DSM-5 criteria.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100295"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12413710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging the gap: A conversion framework for CDR-SB and MoCA scores in Alzheimer's disease and related dementia.","authors":"Babak Haji, Quanwu Zhang, Amir Abbas Tahami Monfared","doi":"10.1016/j.tjpad.2025.100226","DOIUrl":"10.1016/j.tjpad.2025.100226","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objectives: </strong>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.</p><p><strong>Design: </strong>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.</p><p><strong>Setting: </strong>National Alzheimer's Coordinating Center (NACC), aggregating standardized assessments from 35 U.S.-based Alzheimer's Disease Research Centers.</p><p><strong>Participants: </strong>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.</p><p><strong>Intervention: </strong>None; this was a secondary analysis of existing data.</p><p><strong>Measurements: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100226"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12413701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CTAD taskforce: genetic therapies in Alzheimer's disease.","authors":"D Jakabek, A M Isaacs, B De Strooper, M Tuszynski, R Lane, O Uspenskaya, E McDade, M S Rafii, C J Mummery","doi":"10.1016/j.tjpad.2025.100269","DOIUrl":"10.1016/j.tjpad.2025.100269","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100269"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12413703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trajectories of Cardiorespiratory Fitness Measured by Metabolic Equivalents and the Risk of Alzheimer's and Related Dementias.","authors":"Edward Zamrini, Yan Cheng, Peter Kokkinos, Charity J Morgan, Charles Faselis, Helen M Sheriff, Yijun Shao, Xuemei Sui, Ali Ahmed, Qing Zeng","doi":"10.1016/j.tjpad.2025.100222","DOIUrl":"10.1016/j.tjpad.2025.100222","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 %).</p><p><strong>Discussion: </strong>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.</p>","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100222"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12413720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of cardiovascular risk factors on plasma biomarkers in prediction of Alzheimer's and cerebrovascular neuropathology.","authors":"Camilo Bermudez, Jeremy A Syrjanen, Nikki H Stricker, Alicia Algeciras-Schimnich, Naomi Kouri, Walter K Kremers, Ronald C Petersen, Clifford R Jack, 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","doi":"10.1016/j.tjpad.2025.100224","DOIUrl":"10.1016/j.tjpad.2025.100224","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Design: &lt;/strong&gt;Retrospective, case-control study.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Setting: &lt;/strong&gt;Population-based, Olmstead county, Minnesota, USA.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants: &lt;/strong&gt;Three-hundred and fifty-one participants (aged 87.4 ± 7.5 years) with brain autopsy and antemortem plasma biomarker testing.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Measurements: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Understanding how cardiovascular risk factors can modulate plasma biomarkers is important for their interpretation with respect to underlying pathology and their ","PeriodicalId":22711,"journal":{"name":"The Journal of Prevention of Alzheimer's Disease","volume":" ","pages":"100224"},"PeriodicalIF":7.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12413713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}