All women undergo the menopause transition (MT), a neuro-endocrinological process that impacts aging trajectories of multiple organ systems including brain. The MT occurs over time and is characterized by clinically defined stages with specific neurological symptoms. Yet, little is known of how this process impacts the human brain. This multi-modality neuroimaging study indicates substantial differences in brain structure, connectivity, and energy metabolism across MT stages (pre-menopause, peri-menopause, and post-menopause). These effects involved brain regions subserving higher-order cognitive processes and were specific to menopausal endocrine aging rather than chronological aging, as determined by comparison to age-matched males. Brain biomarkers largely stabilized post-menopause, and gray matter volume (GMV) recovered in key brain regions for cognitive aging. Notably, GMV recovery and in vivo brain mitochondria ATP production correlated with preservation of cognitive performance post-menopause, suggesting adaptive compensatory processes. In parallel to the adaptive process, amyloid-β deposition was more pronounced in peri-menopausal and post-menopausal women carrying apolipoprotein E-4 (APOE-4) genotype, the major genetic risk factor for late-onset Alzheimer’s disease, relative to genotype-matched males. These data show that human menopause is a dynamic neurological transition that significantly impacts brain structure, connectivity, and metabolic profile during midlife endocrine aging of the female brain.

Objective.To examine associations between indicators of estrogen exposure from women’s reproductive history and brain MRI biomarkers of Alzheimer’s disease (AD) in midlife.Methods.We evaluated 99 cognitively normal women ages 52+6 years, and 29 men ages 52+7 years, with reproductive history data, neuropsychological testing, and volumetric MRI scans. We used multiple regressions to examine associations between reproductive history indicators, voxel-wise gray matter volume (GMV), memory and global cognition scores, adjusting for demographics and midlife health indicators. Exposure variables were menopause status, age at menarche, age at menopause, reproductive span, hysterectomy status, number of children and pregnancies, use of menopause hormonal therapy (HT) and hormonal contraceptives (HC).Results.All menopausal groups exhibited lower GMV in AD-vulnerable regions as compared to men, with peri-menopausal and post-menopausal groups also exhibiting lower GMV in temporal cortex as compared to the pre-menopausal group. Reproductive span, number of children and pregnancies, use of HT and HC were positively associated with GMV, chiefly in temporal cortex, frontal cortex, and precuneus, independent of age, APOE-4 status, and midlife health indicators. Although reproductive history indicators were not directly associated with cognitive measures, GMV in temporal regions was positively associated with memory and global cognition scores.Conclusions.Reproductive history events signaling more estrogen exposure, such as pre-menopausal status, longer reproductive span, higher number of children, use of HT and HC, were associated with larger GMV in midlife women. Further studies are needed to elucidate sex-specific biological pathways through which reproductive history influences cognitive aging and AD-risk.

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