Abstract:
Background: Background: The age at menopause marks a critical neuroendocrine transition that may influence later-life cognitive health. Earlier estrogen deprivation has been linked to increased neuronal vulnerability, but large-scale population-based data are scarce.
Objective: To investigate the association between age at menopause and dementia risk using real-world data from the TriNetX Global Research Network.
Methods: Methods: We conducted a retrospective cohort study including women aged ≥18 years with a recorded diagnosis of menopause (ICD-10 N95). Participants were classified into two groups: early menopause (<45 years) and typical or late menopause (≥45 years). Women with prior diagnoses of dementia, multiple sclerosis, Parkinson’s disease, epilepsy, or severe traumatic brain injury were excluded. Outcomes included incident dementia (ICD-10 F00-F03, G30, G31.*). Two analyses were performed: an unmatched crude comparison and an age-matched propensity score analysis. Risk ratios (RR) and hazard ratios (HR) were estimated using Cox regression and Kaplan-Meier survival analyses.
Results: Results: In the crude analysis (n=2,681,006), dementia incidence was 3.9% among women with menopause ≥45 years and 0.3% among those with menopause <45 years (HR 11.2, 95% CI 10.4-12.0). After age matching (130,740 per group), the association reversed: early menopause was associated with higher dementia risk (0.6% vs. 0.4%, HR 2.95, 95% CI 2.6-3.3). This indicates that the initial apparent effect was fully confounded by current age, and that early menopause independently predicts dementia.
Conclusion: Conclusion: Early menopause (<45 years) is associated with nearly a threefold higher risk of dementia compared with menopause after age 45, after controlling for age. These findings highlight the need for gender-focused dementia prevention strategies and reinforce the relevance of reproductive history in cognitive aging.Keywords: Menopause, Dementia, Estrogen, TriNetX, Real-world data, Women’s brain health