Few studies focus on sex differences in aging, and even fewer on early antecedents to this critical adult onset problem, even though women are at twice the risk of memory (MEM) deficits with aging than men. Animal studies have demonstrated fetal antecedents to adult MEM circuitry deficits, implicating disruption of the hypothalamic-pituitary-adrenal (HPA) axis on hippocampal (HIPP) and prefrontal cortex (PFC) development, structure and function in adulthood, brain regions that are sexually dimorphic and relatively dense in glucocorticoid and gonadal hormone receptors. The proposed study is based on the premise that the developmental period of the sexual differentiation of the brain in mid-to-late gestation is a critical window during which sex differences in MEM deficits associated with aging arise. We hypothesize that loss of estrogenic support during the menopausal transition, particularly women exposed to fetal HPA disruption, will have significant effects on sexually dimorphic brain regions that impact MEM and working MEM function. We have a rare opportunity to investigate fetal antecedents to sex differences in adult MEM/wMEM deficits in human in vivo studies because the PI and her collaborators have been conducting 40-year follow-up studies of a prenatal cohort, consisting of subjects (now ages 44-51) followed from gestation. We are funded in MH074835 to evaluate adult subjects on multiple domains (e.g., prenatal sera for HPA disruption;adult MEM performance) on 350 discordant siblings, one of whom experienced fetal HPA disruption. In the proposed study, we will re recruit 200 of these same-sex discordant siblings, equally divided by gender, and use functional and structural MRI, diffusion tensor imaging to evaluate white matter abnormalities, and hormonal evaluations to test our hypotheses that fetal HPA disruption and genetic polymorphisms contribute to explaining midlife sex differences in aging of MEM/wMEM circuitries as ovarian function declines, which is THE critical period to study sex-specific MEM deficits. Identifying early hormonal biomarkers (even fetal) of sex-specific vulnerability to cognitive decline will be significant for the development of interventions that would prevent or attenuate age related disability and maintain intact MEM function in women and men. PUBLIC HEALTH RELEVANCE: It is still unclear why women have 1.5-2 times the risk for memory deficits with aging than men. We have a unique opportunity to evaluate in humans the impact of fetal risk factors known to affect aging, on sex-specific adult memory deficits related to loss of estrogenic support. Identifying sex-specific pathophysiology of cognitive decline has important implications for attenuation of suffering worldwide, particularly in women.