Effects of a 24-week resistance exercise program on brain amyloid and Alzheimer’s disease blood-based biomarkers: the AGUEDA randomized controlled trial

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 ( <i>APOE4</i> ) 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 <i>APOE4</i> status on brain Aβ (p for interaction<0.05), with increases observed in <i>APOE4</i> 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.