Earlier menopause associated with less favorable functional, structural neurological outcomes

A longitudinal cohort study published in JAMA Women's Health found that earlier age at menopause was associated with faster cognitive decline, earlier Alzheimer disease (AD) diagnosis, and patterns of brain volume change in older women, with some associations differing depending on whether menopause was spontaneous or surgical. The study sought to address a gap in prior research: Although earlier menopause has previously been linked to cognitive decline, longitudinal data on corresponding brain volume changes over time have been limited.

Researchers used data from the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP), 2 harmonized aging cohorts with up to 18 years of follow-up. Religious Orders Study enrollment began in January 1994, and Rush Memory and Aging Project enrollment ran from September 1997 to April 2005, with follow-up ongoing in both. Data were extracted and analyzed in August 2025. The exposure of interest was age at menopause, examined overall and stratified by menopause type (spontaneous versus surgical).

Outcomes included:

• global and domain-specific cognitive decline
• time to AD diagnosis
• AD neuropathologic change at autopsy
• brain volume trajectories (including total brain volume and white matter hyperintensity volume)

Earlier menopause’s association with neurological outcomes

• Analyses included 2603 women with cognitive data, 1287 with neuropathology at autopsy, and 774 with serial 3T magnetic resonance imaging.
• Mean (SD) age at enrollment was 78.30 (7.85) years; 172 participants (6.6%) were Black or African American and 2400 (92.2%) were 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).
• Earlier menopause age was associated with faster episodic memory decline (β = −0.0014; SE = 0.0005; FDR-corrected P = .03)
• Earlier menopause age was associated with earlier AD diagnosis in the full cohort (time ratio = 0.998; 95% CI, 0.997-0.999; FDR-corrected P = .02).
• The association with AD diagnosis timing was directionally stronger in women with 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).

White matter changes appeared specific to spontaneous menopause

The association between earlier menopause and faster white matter hyperintensity accumulation increased with advancing age but was not observed in women with surgical menopause, a pattern the study authors said points to specificity tied to the gradual hormonal trajectory characteristic of spontaneous menopause rather than the abrupt hormonal loss of surgical menopause.

Associations persisted and intensified decades after the menopausal transition

Rather than fading with time, the associations between earlier menopause age and both functional and structural neurological outcomes persisted and, in some measures, grew stronger decades after the menopausal transition itself, spanning cognitive, clinical, and imaging domains within the same cohort.

“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,” the authors noted.

Reference:

Campagna MP, Schneider JA, Barnes LL, et al. Age at menopause and brain atrophy among older women. JAMA Netw Open. 2026;9(8):e2630973. doi:10.1001/jamanetworkopen.2026.30973