Effects of a 24-week resistance exercise program on Alzheimer's disease brain signatures in cognitively normal older adults: results from the AGUEDA trial.

Objective: To examine the effects of a 24-week resistance exercise (RE) program on Alzheimer's disease (AD) brain signatures in cognitively normal older adults; and to identify moderating factors, assess the association between AD brain signatures changes and cognitive outcomes, including mediation by AD brain signatures Methods: Ninety participants (72±4 years, 58% female) were randomized to a RE group (3 sessions/week, 60 min/session, n=46) or a wait-list control group (CG, n=44). T1- and diffusion-weighted MRI (3T) were acquired pre- and post-intervention. AD thickness/volume and gray matter mean diffusivity (GMMD) signatures were derived from cortical and hippocampal regions. Baseline adjusted mixed models tested intervention effects. Moderators included age, sex, education, APOE4 status, amyloid beta (Aβ) status, and baseline AD signatures. Associations with cognition and possible mediators were explored. Results: The RE group showed reduction in the AD thickness/volume signature (-0.23 standardized mean difference [SMD]; 95% CI, -0.43 to -0.02), but no effect on the AD GMMD signature (0.08 SMD; 95% CI, -0.13 to 0.29) vs CG. Aβ status moderated the effect, with Aβ-positive participants in the RE group showing a larger reduction in AD thickness/volume signature compared to the CG (-0.64 SMD; 95% CI, -1.09 to -0.18), whereas no effect was found in Aβ-negative participants. AD thickness/volume signature reductions were associated with better executive function, and AD GMMD signature reductions with attentional/inhibitory control improvements. Changes in AD signatures did not mediate changes in cognition. Conclusion: A 24-week RE intervention reduced AD thickness/volume signature, especially in Aβ-positive participants, and was linked to improved executive function. No effects were observed on the AD GMMD signature. These findings suggest RE may support brain health by delaying structural changes characteristic of preclinical stages of AD. Further research is needed to replicate and confirm these results.