To examine associations between indicators of estrogen exposure from women's reproductive history and brain MRI biomarkers of Alzheimer disease (AD) in midlife.

We evaluated 99 cognitively normal women 52 ± 6 years of age and 29 men 52 ± 7 years of age with reproductive history data, neuropsychological testing, and volumetric MRI scans. We used multiple regressions to examine associations among reproductive history indicators, voxel-wise gray matter volume (GMV), and 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, and use of menopause hormonal therapy (HT) and hormonal contraceptives (HC).

All menopausal groups exhibited lower GMV in AD-vulnerable regions compared to men, with perimenopausal and postmenopausal groups also exhibiting lower GMV in temporal cortex compared to the premenopausal group. Reproductive span, number of children and pregnancies, and use of HT and HC were positively associated with GMV, chiefly in temporal cortex, frontal cortex, and precuneus, independent of age, APOE ε4 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.

Reproductive history events signaling more estrogen exposure such as premenopausal status, longer reproductive span, higher number of children, and use of HT and HC were associated with larger GMV in women in midlife. Further studies are needed to elucidate sex-specific biological pathways through which reproductive history influences cognitive aging and AD risk.