Effects of a 24-week resistance exercise program on Alzheimer's disease brain signatures in cognitively unimpaired older adults: a secondary analysis of the AGUEDA randomized controlled trial.

BACKGROUND: Brain imaging markers may help detect early cognitive decline and Alzheimer's disease (AD). Although exercise-related effects on AD-specific brain signatures remain unclear. OBJECTIVE: To examine the effects of a 24-week resistance exercise (RE) program on AD brain signatures in cognitively unimpaired older adults, to explore potential moderators and to assess associations with cognition, including mediation effects. METHODS: This secondary analysis of a single-site, two-arm, single-blinded randomized controlled trial included 90 participants (72 ± 4 years; 58% female) randomly assigned by a blind external researcher to an RE group (3 sessions/week, 60 min/session, n = 46) or a wait-list control group (CG, n = 44). T1- and diffusion-weighted MRI were acquired at baseline and post-intervention. Primary outcomes were thickness/volume and grey matter mean diffusivity (GMMD) signatures, derived from cortical and hippocampal regions. Moderators included age, sex, education, multimorbidity, apolipoprotein E ϵ4 status, amyloid beta (Aβ) status and baseline AD brain signatures. Secondary outcomes included cognitive function. Outcome measures and analyses were conducted by staff blinded to intervention assignment. RESULTS: Compared with the CG, the RE group showed a reduction in the thickness/volume signature (-0.23 standardized mean difference [SMD]; 95% CI, -0.43 to -0.02), but no effect on the GMMD signature (0.08 SMD; 95% CI, -0.13 to 0.29). Aβ-status moderated the effect, as Aβ-positive participants in the RE group showed a larger reduction in the thickness/volume signature than those in the CG (-0.64 SMD; 95% CI, -1.09 to -0.18), whereas no effect was observed in Aβ-negative participants. Thickness/volume and GMMD reductions were associated with improvements in executive function and attentional/inhibitory control, respectively. Changes in AD signatures did not mediate cognitive outcomes. CONCLUSION: Our findings suggest that reductions in the macrostructural AD signature following a 24-week RE program may reflect adaptive, rather than detrimental, brain changes, particularly in Aβ-positive older adults, as these changes were associated with improved executive function. TRIAL REGISTRATION: Registered on Clinicaltrials.gov (Identifier: NCT05186090).