Reproductive Lifespan and Hormonal Therapy in Relation to Later-Life Neurovascular Health in Community-Dwelling Older Women.

Background

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Objectives

Women are disproportionately affected by Alzheimer disease (AD), a vulnerability that may relate to estrogen fluctuations across the lifespan. Estrogen has neuroprotective and vasoprotective effects, suggesting that lifetime estrogen exposure may influence both AD-related neurodegeneration and cerebrovascular health. However, its association with late-life vascular and neurodegenerative brain changes remains unclear. We aimed to examine the associations of lifelong estrogen exposure-endogenous (reproductive span) and exogenous (oral contraceptives [OCs], menopausal hormone therapy [MHT])-with late-life vascular brain injury and AD-related atrophy and explore apolipoprotein-ε4 (APOE-ε4) effects.

Methods

This population-based study included cognitively unimpaired women from the Gothenburg H70-1944 Birth Cohort who underwent brain MRI at age 70 and again 5 years later. Reproductive lifespan was calculated as age at menopause or oophorectomy minus age at menarche. OC and MHT use were categorized as ever vs never users. Outcomes included cerebral small vessel disease (SVD), AD-related cortical thickness, and white matter integrity (fractional anisotropy). SVD burden was a composite score derived from white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), and perivascular spaces (PVSs) (range 0-4). Linear, multinomial, and mixed-effects regression models were adjusted for relevant confounders and stratified by APOE-ε4.

Results

Among 352 women (mean age 70 years), longer reproductive span was associated with lower SVD burden (OR = 0.92, 95% CI 0.86-0.99). MHT use was associated with fewer PVSs and CMBs. OC and MHT use were associated with greater white matter integrity, with combined use showing the highest fractional anisotropy compared with nonusers (β = 0.45, 95% CI 0.12-0.78). No multiplicative interaction between OCs and MHT was observed, although joint exposure analyses suggested cumulative effects. MHT use was associated with greater AD-related cortical thickness among APOE-ε4 carriers only (β = 0.38, 95% CI 0.01-0.76). Longer estrogen exposure was associated with stable cortical thickness and WMH trajectories over time.

Discussion

Greater lifetime estrogen exposure, both endogenous and exogenous, was associated with lower cerebrovascular pathology in women and, among APOE-ε4 carriers, greater cortical thickness in AD-vulnerable regions. These findings support the potential role of cerebrovascular mechanisms linking estrogen exposure to brain aging. Limitations included observational design and self-reported, binary estrogen exposure. Potential cognitive effects require further studies.