Study of Menopause and Resistance Training for Brain Health (SMART brain): a randomized controlled trial

Neuropathological changes associated with Alzheimer’s disease begin to manifest during midlife. In females, this period coincides with perimenopause and early postmenopause, two distinct, critical reproductive stages characterized by dramatic changes in hormones, cognition, and cerebrovascular function. Exercise is a promising lifestyle strategy to promote brain health; no randomized controlled trial (RCT) has examined the effect of resistance training (RT) on cognition across these two reproductive stages, or whether reproductive stage moderates the efficacy of exercise for brain health. This is a pilot sub-study of an assessor-blinded RCT of 40 perimenopausal and early postmenopausal females (45–60 years) randomized to a 9-month, twice-weekly, supervised progressive RT group or wait-list control (CON) group, stratified by menopause hormone therapy and reproductive stage. Thirty-five females volunteered for this sub-study (RT = 17, CON = 18). The primary outcome was cognitive function and the secondary outcome was task-induced cerebral hemodynamics measured using functional near-infrared spectroscopy (fNIRS). Analysis of covariance tested main and interaction effects of experimental group (RT, CON) and reproductive stage (perimenopause, early postmenopause), adjusting for baseline performance and relevant covariates. Data were analyzed with imputation and complete-case approaches. Significant experimental group-by-reproductive stage interactions were observed for episodic memory and the executive function task assessing set-shifting (all p’s<0.05). Planned contrasts showed that RT improved memory in perimenopause, whereas RT improved set-shifting in early postmenopause. Additionally, a significant group-by-stage interaction was found for the hemodynamic response function (all p’s<0.05), with RT increasing task-induced total hemoglobin concentration in the left dorsolateral prefrontal cortex in early postmenopause only. No significant hemodynamic effects were observed in perimenopause. Resistance training led to reproductive stage–specific improvements in cognition and task-induced cerebral hemodynamics during midlife. These preliminary findings from this pilot study suggest that perimenopause and early postmenopause may represent distinct windows of exercise responsiveness for brain health, highlighting the importance of considering reproductive stage of females in exercise trials and supporting the need for future studies with larger sample sizes to examine resistance training for protecting brain health in midlife. The STOP-EM trial protocol (parent study) was registered at ClinicalTrials.gov (NCT05961371), December 15 2024.