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.

After advanced age, female sex is the major risk factor for late-onset Alzheimer’s disease (AD), the most common cause of dementia affecting over 24 million people worldwide. The prevalence of AD is higher in women than in men, with postmenopausal women accounting for over 60% of all those affected. While most research has focused on gender-combined risk, emerging data indicate sex and gender differences in AD pathophysiology, onset, and progression, which may help account for the higher prevalence in women. Notably, AD-related brain changes develop during a 10–20 year prodromal phase originating in midlife, thus proximate with the hormonal transitions of endocrine aging characteristic of the menopause transition in women. Preclinical evidence for neuroprotective effects of gonadal sex steroid hormones, especially 17β-estradiol, strongly argue for associations between female fertility, reproductive history, and AD risk. The level of gonadal hormones to which the female brain is exposed changes considerably across the lifespan, with relevance to AD risk. However, the neurobiological consequences of hormonal fluctuations, as well as that of hormone therapies, are yet to be fully understood. Epidemiological studies have yielded contrasting results of protective, deleterious and null effects of estrogen exposure on dementia risk. In contrast, brain imaging studies provide encouraging evidence for positive associations between greater cumulative lifetime estrogen exposure and lower AD risk in women, whereas estrogen deprivation is associated with negative consequences on brain structure, function, and biochemistry. Herein, we review the existing literature and evaluate the strength of observed associations between female-specific reproductive health factors and AD risk in women, with a focus on the role of endogenous and exogenous estrogen exposures as a key underlying mechanism. Chief among these variables are reproductive lifespan, menopause status, type of menopause (spontaneous vs. induced), number of pregnancies, and exposure to hormonal therapy, including hormonal contraceptives, hormonal therapy for menopause, and anti-estrogen treatment. As aging is the greatest risk factor for AD followed by female sex, understanding sex-specific biological pathways through which reproductive history modulates brain aging is crucial to inform preventative and therapeutic strategies for AD.