Earlier Menopause Age Linked to Less Favorable Late-Life Brain Aging Outcomes

Earlier menopause age was associated with less favorable cognitive and structural brain aging outcomes decades later, according to results from a longitudinal cohort study published in JAMA Network Open.

The study evaluated data from the Religious Orders Study and the Rush Memory and Aging Project, 2 longitudinal aging cohorts with annual clinical evaluations, neuropsychological testing, brain donation at death, and available MRI data in a subset of participants. The analysis included 2603 women with longitudinal cognitive data, 1287 with neuropathologic data at autopsy, and 774 with serial 3T MRI data.

The primary exposure was self-reported age at menopause, evaluated overall and stratified by menopause type. Menopause was classified as spontaneous or surgical based on self-reported data. Reproductive lifespan, defined as age at menopause minus age at menarche, was evaluated as an exploratory secondary exposure.

Primary outcomes included global and domain-specific cognitive decline, time to Alzheimer disease (AD) diagnosis, AD neuropathologic change at autopsy, and brain volume trajectories, including total brain volume and white matter hyperintensity volume (WMHV). Models were adjusted for demographic, clinical, and genetic covariates, including age, education, race, body mass index, smoking pack-years, menopausal hormone therapy use, and apolipoprotein ε4 (APOE ε4) status.

Cognitive, Clinical, and MRI Findings

• The full cognitive cohort included 2603 women with a mean enrollment age of 78.3 years.
• Among participants, 1753 women had spontaneous menopause and 850 had surgical menopause.
• Women with surgical menopause had earlier menopause than those with spontaneous menopause, with median ages of 43.0 years and 50.0 years, respectively.
• Earlier menopause age was associated with faster global cognitive decline (false discovery rate [FDR]–corrected P=.04).
• Earlier menopause age was also associated with faster episodic memory decline (FDR-corrected P=.03).
• Earlier menopause age was associated with shorter time to AD diagnosis in the full cohort (time ratio, 0.998 per year earlier menopause age; 95% CI, 0.997 to 0.999; FDR-corrected P=.02).
• AD neuropathologic change at autopsy was not significantly associated with menopause timing in the full cohort after correction for multiple comparisons.
• In serial MRI analyses, earlier menopause age was associated with total brain volume trajectories in the full cohort, although the effect size was below conventional thresholds for a small association and was interpreted cautiously by the investigators.
• Among women with spontaneous menopause, earlier menopause age was associated with faster WMHV accumulation, representing the largest MRI effect size observed in the study (f²=0.30; FDR-corrected P<.001).
• The WMHV association was not observed among women with surgical menopause.
• Exploratory analyses did not identify significant moderation by menopausal hormone therapy use for brain volume trajectories.

Potential Implications for Clinical Practice

The findings suggest that menopause timing may be relevant to late-life brain health risk stratification, particularly as a midlife factor identifiable decades before cognitive or structural changes may become apparent. For neurologists, the results may be most relevant when considering sex-specific and reproductive health factors in dementia risk assessment, research enrollment, and counseling about long-term brain health.

Source

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