A Case for estradiol: younger brains in women with earlier menarche and later menopause

The transition to menopause is marked by a gradual decrease of estradiol. Concurrently, the risk of dementia in women increases around menopause, suggesting that estradiol (or the lack thereof) plays a role in the development of dementia and other age-related neuropathologies. Here, we set out to investigate whether there is a link between brain aging and estradiol-associated events, such as menarche and menopause. For this purpose, we applied a well-validated machine learning approach to analyze both cross-sectional and longitudinal data from a sample of 1,006 postmenopausal women who underwent structural magnetic resonance imaging twice, approximately 2 years apart. We observed less brain aging in women with an earlier menarche, a later menopause, and a longer reproductive span (i.e., the time interval between menarche and menopause). These effects were evident both cross-sectionally and longitudinally, supporting the notion that estradiol has neuroprotective properties and contributes to brain preservation. However, further research is required because the observed effects were small, estradiol was not directly measured, and other factors may modulate female brain health. Future studies might benefit from incorporating actual estradiol (and other hormone) measures, as well as considering genetic predispositions and lifestyle factors alongside indicators of brain aging to deepen our understanding of estradiol's role in maintaining brain health. Additionally, including more diverse study populations (e.g., varying in ethnicity, socioeconomic status, and health status) in follow-up research would enhance the generalizability and applicability of these findings.