Longer Estrogen Exposure Correlates with a Lesser Degree of Neurodegeneration
The present natural human lifespan is determined by an evolved balance between (a) reduced tissue maintenance that slowly leads to tissue failure, frailty, and death versus (b) continued tissue maintenance that steadily increases the risk of cancer and abrupt death. A growing burden of mutational damage throughout the body with advancing age makes the activities of cell maintenance (particularly replication in stem cell populations) ever more likely to result in cancer. That risk of cancer is lowered by reduced tissue maintenance, at the cost of a slower mortality via other causes. One of the mechanisms by which tissue maintenance is dialed down in later life is a reduction in sex hormone production. This occurs slowly over time in older men, and fairly abruptly in older women at menopause. The size of this effect can be observed in data such as that presented here, showing that women who either undergo menopause later or were using hormone therapy exhibit a reduced burden of neurodegeneration.
Women are disproportionately affected by Alzheimer's 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, menopausal hormone therapy) - with late-life vascular brain injury and AD-related atrophy and explore apolipoprotein-ε4 (APOE-ε4) effects.
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. Among 352 women (mean age 70 years), longer reproductive span was associated with lower cerebral small vessel disease burden (odds ratio = 0.92). Menopausal hormone therapy use was associated with fewer perivascular space enlargements and cerebral microbleeds. Oral contraceptives and menopausal hormone therapy use were associated with greater white matter integrity, with combined use showing the highest fractional anisotropy compared with nonusers (β = 0.45). No multiplicative interaction between oral contraceptives and menopausal hormone therapy was observed, although joint exposure analyses suggested cumulative effects. Menopausal hormone therapy use was associated with greater AD-related cortical thickness among APOE-ε4 carriers only (β = 0.38). Longer estrogen exposure was associated with stable cortical thickness and white matter hyperintensity trajectories over time.