Age at Menopause and Brain Atrophy Among Older Women

Importance: Earlier menopause has been linked to increased cognitive decline, but longitudinal data regarding corresponding volumetric brain changes are scarce, and the lasting associations of menopause timing on brain atrophy rates that accompany cognitive decline in women remain unknown. Objective: To evaluate whether menopause age is associated with cognitive decline, Alzheimer disease (AD) onset, and brain volume trajectories in older women and whether this differs by menopause type. Design, Setting, and Participants: Longitudinal cohort study using the Religious Orders Study and Rush Memory and Aging Project with up to 18 years of follow-up. Religious Orders Study enrollment began January 1994 and Rush Memory and Aging Project enrollment ran September 1997 to April 2005; follow-up is ongoing in both. Data were extracted and analyzed in August 2025. Analyses included 2603 women with cognitive data, 1287 with neuropathology at autopsy, and 774 with serial 3T magnetic resonance imaging. Exposures: Age at menopause, examined overall and stratified by menopause type (spontaneous vs surgical). Main Outcomes and Measures: Global and domain-specific cognitive decline, time to AD diagnosis, AD neuropathologic change at autopsy, and brain volume trajectories including total brain volume and white matter hyperintensity volume, modeled using linear mixed-effects, accelerated failure time, proportional odds, and inverse-probability-weighted generalized additive mixed models with a prespecified 3-family Benjamini-Hochberg correction. Results: From a total of 2603 women (mean [SD] age of enrollment, [78.30 [7.85], ; 172 [6.6%] Black or African American and 2400 [92.2%] White non-Hispanic), earlier menopause age was associated with faster global cognitive decline (β = -0.0009 SD per year earlier menopause age; SE = 0.0004; false-discovery rate [FDR]-corrected P = .04), faster episodic memory decline (β = -0.0014; SE = 0.0005; FDR-corrected P = .03), and earlier AD diagnosis in the full cohort (time ratio = 0.998; 95% CI, 0.997-0.999; FDR-corrected P = .02); associations were directionally stronger in surgical menopause (time ratio = 1.000; 95% CI, 0.998-1.000; P = .008). Earlier menopause age was associated with substantially faster white matter hyperintensity volume accumulation in women with spontaneous menopause (f2 = 0.30; FDR-corrected P < .001), an association that increased with advancing age and was absent in surgical menopause, indicating specificity to the gradual hormonal trajectory of spontaneous menopause. Conclusions and Relevance: In this cohort study of older women, earlier menopause was associated with less favorable functional and structural neurological outcomes, with associations persisting and intensifying decades after the menopausal transition. These findings position menopause age as a midlife-identifiable marker for risk stratification, offering a window for targeted prevention before structural or cognitive changes become apparent.