Women’s brain aging: effects of sex-hormone exposure, pregnancies, and genetic risk for Alzheimer’s disease


Sex hormones such as estrogen fluctuate across the female lifespan, with high levels during re-productive years and natural decline during the transition to menopause. Women’s exposure toestrogen may influence their heightened risk of Alzheimer’s disease (AD) relative to men, but littleis known about how it affects normal brain aging. Recent findings from the UK Biobank demon-strate less apparent brain aging in women with a history of multiple childbirths, highlighting apotential link between sex-hormone exposure and brain aging. We investigated endogenous andexogenous sex-hormone exposure, genetic risk for AD, and neuroimaging-derived biomarkers forbrain aging in 16,854 middle to older-aged women. The results showed that as opposed to parity,higher cumulative sex-hormone exposure was associated with more evident brain aging, indicatingthat i) high levels of cumulative exposure to sex-hormones may have adverse effects on the brain,and ii) beneficial effects of pregnancies on the female brain are not solely attributable to modula-tions in sex-hormone exposure. In addition, for women using hormonal replacement therapy (HRT),starting treatment earlier was associated with less evident brain aging, but only in women with agenetic risk for AD. Genetic factors may thus contribute to how timing of HRT initiation influenceswomen’s brain aging trajectories.

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