“Impact of Depression on Alzheimer's disease: Prenatal Immune Origins and Shared Impact of Sex” Project Summary With the substantial increase in aging of the population, early prevention of Alzheimer’s disease (AD) is one of the most important public health and economic challenges of our time. AD is associated with major depressive disorder (MDD), and both have twice the frequency in women than men. However, the shared pathophysiology that underlies MDD and AD is not well known. We will test the hypothesis that this shared risk has fetal origins that involve abnormalities in immune-stress and vascular pathways with sex-dependent consequences. We are uniquely poised to examine this for the first time in humans using our 60-year prospective prenatal cohort of adults, followed since 2nd/3rd trimesters of gestation and tested recently at ages 44-57 in MH090291. In that study, we investigated the fetal programming of sex differences in memory circuitry aging, following 212 discordant siblings (one exposed to preeclampsia (PE) or fetal growth restriction (FGR) and one unexposed) wherein we showed PE/FGR associated with maternal prenatal immune activation abnormalities in TNF-, IL- 10, and IL-6. We propose to follow these siblings further to investigate later midlife memory decline over 8 years, neurovascular dysfunction, and preclinical AD pathology assessed as amyloid deposition. We will use the same multimodal imaging as in MH090291 (structural, functional, and diffusion brain imaging-- sMRI/fMRI/dMRI) and same measures of verbal learning/memory, coupled with new measures of neurovascular function based on retinal imaging, novel transcriptomic analyses in the adult offspring’s peripheral blood mononuclear cells measuring innate immune gene expression, and amyloid deposition based on PiB PET imaging. We postulate that prenatal maternal biomarkers, indicating in utero immune disruptions at mid-gestation, coupled with innate immune gene expression, will be related to sex-dependent adult outcomes in later midlife. Further, we will test whether associations between prenatal inflammatory biomarkers and sex- dependent AD risk and neurovascular dysregulation are mediated by sex-dependent risk for MDD. Our lifespan perspective is an innovative approach that will identify potential therapeutic targets for AD associated with MDD and vascular function that are sex-dependent and can be applied to early periods for intervention prior to disease onset.