Towards an understanding of women's brain aging: the immunology of pregnancy and menopause

Abstract

Women are at significantly greater risk of developing Alzheimer's disease and show higher prevalence of autoimmune conditions relative to men. Women's brain health is historically understudied, and little is therefore known about the mechanisms underlying epidemiological sex differences in neurodegenerative diseases, and how female-specific factors may influence women's brain health across the lifespan. In this review, we summarize recent studies on the immunology of pregnancy and menopause, emphasizing that these major immunological and hormonal transition phases may play a critical part in women's brain aging trajectories.

Sex- and age-specific associations between cardiometabolic risk and white matter brain age in the UK Biobank cohort

“…Some studies have reported genotype-specific effects, with a longer reproductive span conferring greater risk in APOE4 carriers [130], and older brain age linked to greater menopausal levels of estradiol in APOE4 carriers and lower levels in non-carriers [131]. These studies point to a possible modulatory role of estrogen exposure [132], typically having beneficial effects, but potentially becoming neurotoxic in the context of greater AD pathology [133] or diseased cell populations (i.e., 'healthy cell' hypothesis [134]). While future studies including detailed data about the menopausal transition (i.e., pre-, peri, post menopause) as well as specific measures of AD-related brain pathology [135] are required to test these hypotheses, our findings showed a small but significant association between earlier menopause transition and higher WM BAG in the current cohort, in line with studies linking a shorter reproductive span to risk for neurodegeneration [127,130,136,137,138,139].…”

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

“…In contrast, the transition to menopause marks a period of decline in ovarian hormone levels and can foster a pro‐inflammatory phenotype involving increased risk for autoimmune activity and neuronal injury. Beneficial immune adaptations in pregnancy could potentially have long‐lasting effects, improving the response to menopause‐related inflammation, and subsequently leading to more favorable brain aging trajectories in multiparous women (Barth & de Lange, 2020; Fox et al, 2018; Mishra & Brinton, 2018). Another mechanism through which pregnancy may have long‐lasting effects on maternal physiology is fetal microchimerism—the presence of fetal cells in the maternal body (Boddy et al, 2015).…”

“…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. Brainage 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, , 2018Cole & 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.…”

A history of previous childbirths is linked to women’s white matter brain age in midlife and older age

“…However, oestrogen exposure has also been associated with GM atrophy [82] and higher rates of ventricular expansion in menopausal women [83], and some evidence suggests that genetic factors may influence how oestrogen exposure affects brain health [54,84,85]. Beside oestrogen, other hormones such as progesterone, prolactin, oxytocin, and cortisol also fluctuate during pregnancy and may regulate WM plasticity [86,87,88]. While the influence of hormone exposure on brain ageing trajectories is currently unclear, other pregnancy-induced adaptations such as the proliferation of regulatory T cells or fetal microchimerism may also represent mechanisms underlying potential long-term benefits of pregnancy on brain ageing (for a review see [86]).…”

“…Beside oestrogen, other hormones such as progesterone, prolactin, oxytocin, and cortisol also fluctuate during pregnancy and may regulate WM plasticity [86,87,88]. While the influence of hormone exposure on brain ageing trajectories is currently unclear, other pregnancy-induced adaptations such as the proliferation of regulatory T cells or fetal microchimerism may also represent mechanisms underlying potential long-term benefits of pregnancy on brain ageing (for a review see [86]). Future studies may target the links between hormone-and immune-related neuroplasticity in pregnancy, and the potential effect of these processes on women's brain ageing trajectories.…”