| Sumario: | 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).
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