Women's brain aging: Effects of sex‐hormone exposure, pregnancies, and genetic risk for Alzheimer's disease

Abstract

Sex hormones such as estrogen fluctuate across the female lifespan, with high levels during reproductive years and natural decline during the transition to menopause. Women's exposure to estrogen may influence their heightened risk of Alzheimer's disease (AD) relative to men, but little is known about how it affects normal brain aging. Recent findings from the UK Biobank demonstrate less apparent brain aging in women with a history of multiple childbirths, highlighting a potential link between sex-hormone exposure and brain aging. We investigated endogenous and exogenous sex-hormone exposure, genetic risk for AD, and neuroimaging-derived biomarkers for brain 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, indicating that 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 modulations in sexhormone 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 a genetic risk for AD. Genetic factors may thus contribute to how timing of HRT initiation influences women's brain aging trajectories.

Sex differences in brain aging among adults with family history of Alzheimer’s disease and APOE4 genetic risk

“…Thus, higher late-life BMI might be associated with greater circulating estrogen which might be neuroprotective, particularly in post-menopausal women in which the ovaries cease to become the primary source of estrogen release. Importantly, it is critical to investigate whether different sources of estrogen exposure (e.g., age at menarche and menopause, time since menopause, and duration of hormone replacement therapy) and the role of female-specific hormonal transitions, such as parity, differentially contributes to brain aging in women ( de Lange et al, 2020a , de Lange et al, 2020b ).…”

Linking objective measures of physical activity and capability with brain structure in healthy community dwelling older adults

“…The results might be related to the postmenopausal hormonal changes (Dalal & Agarwal, 2015). A recent study demonstrated that higher estimated levels of sex-hormone exposure was associated with higher brain age in women (de Lange et al, 2020b). In addition, an interaction between hormone replacement therapy and fitness on age related decline in gray matter volume has been demonstrated (Erickson et al, 2007), indicating increased neuroprotective effect of fitness in combination with hormone replacement treatment for post-menopausal women.…”

The maternal brain: Region‐specific patterns of brain aging are traceable decades after childbirth

“…Brain‐age prediction was used to derive estimates of global brain aging, which was analyzed in relation to number of previous (live) childbirths in 8,880 newly added UK Biobank participants. Brain‐age prediction is commonly used to estimate an individual's age based on their brain characteristics (Cole & Franke, 2017), and individual variation in “brain age” estimates has been associated with a range of clinical and biological factors (Cole, 2020; Cole et al, 2017, 2018; Cole & Franke, 2017; Cole, Marioni, Harris, & Deary, 2019; de Lange, Anatürk, et al, 2020; de Lange, Barth, et al, 2020; Franke & Gaser, 2019; Kaufmann et al, 2019; Smith, Vidaurre, Alfaro‐Almagro, Nichols, & Miller, 2019). As compared to MRI‐derived measures such as cortical volume or thickness, brain‐age prediction adds a dimension by capturing deviations from normative aging trajectories identified by machine learning.…”