Reproductive lifespan and hormonal therapy in relation to later-life neurovascular health: A population-based study of women in the Gothenburg H70-1944 Birth Cohort

Abstract

Background: Women face greater vulnerability to dementia and Alzheimer's disease (AD), potentially due to estrogen fluctuations across the lifespan. However, its role in vascular brain health is unclear. We investigated associations between lifelong estrogen exposure -endogenous (reproductive span) and exogenous (oral contraceptives [OC], menopausal hormone therapy [MHT])- and late-life vascular brain injury, AD-related atrophy, and APOE4 modification. Methods and findings: We included 352 cognitively unimpaired 70-year-old women from the Gothenburg H70-1944 Birth Cohort with brain MRI and 5-year follow-up. Reproductive lifespan was calculated as age at menopause or oophorectomy minus age at menarche. OC and MHT use were self-reported. Outcomes included cerebral small vessel disease (SVD), AD-related cortical thickness, and white-matter integrity (fractional anisotropy). Linear and multinomial regression and mixed-effects models were adjusted for confounders and stratified by APOE4. Longer reproductive span (OR=0.90 [95%CI 0.83-0.98]) and MHT use (OR=0.43 [95% CI 0.20-0.92]) were linked to lower SVD burden, particularly fewer perivascular spaces and microbleeds. OC and MHT were associated with greater white matter integrity, with additive use throughout life showing the highest fractional anisotropy (OR=0.45 [95% CI 0.12-0.78]). MHT use was associated with greater thickness in areas often affected in AD among APOE4 carriers (beta=0.38 [95% CI 0.01-0.76]) but not in non-carriers. Longer estrogen exposure was linked to stable cortical thickness and WMH trajectories over time. Conclusions: Extended estrogen exposure throughout life-both endogenous and exogenous-appear to support late-life cerebrovascular health in women, with potential genotype-specific neuroprotective effects. Given the current absence of sex-specific prevention guidelines for cognitive disorders, future research should clarify estrogen's long-term impact on brain health and cognition to inform personalized medicine.