We examined whether a 24-week resistance training program influenced brain amyloid-β (Aβ) and Alzheimer’s Disease (AD)-related blood-based biomarkers. Ninety cognitively normal, physically inactive older adults aged 65–80 years were randomly allocated to a 24-week resistance training program (three ∼60-min supervised sessions/week) or a wait-list control group. Primary analyses assessed exercise-induced changes in brain Aβ (Centiloid values) and plasma ptau217/Aβ1-42 IPMS ratio. Secondary analyses examined ptau217/Aβ42 SIMOA ratio, ptau217, ptau181 and Aβ42/40, as well as potential interactions with sex, age, education, apolipoprotein ε4 (APOE4) status, amyloid PET-positivity, and comorbidities. The intervention produced no significant differences on brain Aβ or AD-related blood-based biomarkers (p>0.05) compared to the control group. However, the ptau217/Aβ1–42 IPMS ratio showed a small, non-significant increase in the control group (SMD = 0.162; 95% CI: −0.159 to 0.483) while remaining stable in the exercise group (SMD = 0.01; 95% CI: −0.291 to 0.310) with a similar trend for ptau217/Aβ42 SIMOA. Moderator analyses indicated differential responses by amyloid PET-positivity and APOE4 status on brain Aβ (p for interaction<0.05), with increases observed in APOE4 carriers and amyloid PET–positive individuals in the control group, whereas those allocated to the exercise intervention reduced their levels. The specificity observed within our subgroups suggests that resistance exercise may serve as a targeted intervention to modulate AD pathophysiology, raising new questions regarding its broader role in the delay of the disease in vulnerable populations.

KIE has consulted for MedRhythms, Inc. and NeoAuvra, Inc. TKK has consulted for Quanterix Corporation, SpearBio Inc., Neurogen Biomarking LLC., and Alzheon, has served on advisory boards for Siemens Healthineers, Neurogen Biomarking LLC. and Alzheon (which may come with minority stock equity interest/stock options), outside the submitted work. He has received in-kind research support from Janssen Research Laboratories, SpearBio Inc., and Alamar Biosciences, as well as meeting travel support from the Alzheimer's Association and Neurogen Biomarking LLC., outside the submitted work. TKK has received royalties from Bioventix for the transfer of specific tau antibodies and assays to third party organizations. He has received honoraria for speaker/grant review engagements from the NIH, UPENN, UW–Madison, the Cherry Blossom symposium, the HABS–HD/ADNI4 Health Enhancement Scientific Program, Advent Health Translational Research Institute, Brain Health conference, Barcelona–Pittsburgh conference, the International Neuropsychological Society, the Icahn School of Medicine at Mount Sinai and the Quebec Center for Drug Discovery, Canada, all outside of the submitted work. TKK serves/has served as a guest editor for npj Dementia, as an invited member of the World Health Organization committee to develop preferred product characteristics for blood-based biomarker diagnostics for Alzheimer's disease, as an executive committee member for the Human Amyloid Imaging (HAI) conference, as an elected member of the NACC ADRCs Steering Committee, as co-director of the NACC ADRCs Biofluid Biomarker Working Group, and as a member of the Alzheimer's Association committees to develop Appropriate Use Criteria for clinical use of blood-based biomarkers, and treatment related amyloid clearance. TKK is an inventor on several patents and provisional patents regarding biofluid biomarker methods, targets and reagents/compositions, that may generate income for the institution and/or self should they be licensed and/or transferred to another organization. These include WO2020193500A1: Use of a ps396 assay to diagnose tauopathies; 63/679,361: Methods to Evaluate Early–Stage Pre–Tangle TAU Aggregates and Treatment of Alzheimer's Disease Patients; 63/672,952: Method for the Quantification of Plasma Amyloid–Beta Biomarkers in Alzheimer's Disease; 63/693,956: Anti–tau Protein Antigen Binding Reagents; and 2450702–2: Detection of oligomeric tau and soluble tau aggregates. The rest of the authors have nothing to declare.

NCT05186090

https://github.com/aguedaprojectugr

This work was supported by grants RTI2018-095284-J-I00, PID2022-137399OB-I00 and CNS2024-154835 funded by MCIN/AEI/10.13039/501100011033/ and "ERDF A way of making Europe", and grant RYC2019-027287-I funded by MCIN/AEI/10.13039/501100011033/ and "ESF Investing in your future". M.O-R is supported by the Spanish Ministry of Science, Innovation and Universities (FPU 22/02476). TKK and the Karikari Laboratory members were supported by NIH/NIA (R01 AG083874, U24AG082930, P30 AG066468, RF1 AG077474, R01 AG083156, R37 AG023651, R01 AG025516, R01 AG073267, R01 AG075336, R01 AG072641, P01 AG025204), NIH/NINDS (U01 NS131740, U01 NS141777), NIH/NIMH (R01 MH108509), Aging Mind Foundation (DAF2255207), DoD (HT94252320064), the Anbridge Charitable Fund, and a professorial endowment from the Department of Psychiatry, University of Pittsburgh. This work is part of a Ph.D. Thesis conducted in the Biomedicine Doctoral Studies of the University of Granada, Spain.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The trial protocol was approved by the Research Ethics Board of the Andalusian Health Service (CEIM/CEI Provincial de Granada; #2317–N–19) on May 25th, 2020

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The datasets generated and/or analyzed during the current study are not publicly available due to ethical and institutional restrictions but are available from the corresponding authors on reasonable request.