Association of the in Utero Exposome with Life-Course Cognition and Prodromal Alzheimer's Disease in Midlife. - We propose to discover opportunities for Alzheimer’s Disease (AD) prevention at multiple points in the life- course: before birth, adolescence, and in midlife. We hypothesize that in utero exposure to environmental toxicants leads to cognitive dysfunction in midlife that is accompanied by changes in the serum metabolome and blood biomarkers associated with cognitive dysfunction and prodromal AD. We propose that metabolomics will reveal novel, actionable midlife biomarkers for AD prevention for persons at increased risk for AD. Our previous studies show that decline in cognition is linked to decline in plasma glutathione (GSH), which is best represented in stored plasma by associated changes in pyrimidine and mitochondrial energy metabolism; and that mild cognitive impairment is linked to GSH-related methionine and cysteine metabolism, pathways linked to UDP-sugars (pyrimidine and galactose metabolism) and tyrosine metabolism. Each of these pathways is actionable, providing a secure foundation to test these pathways as mechanisms for biological responses to environmental exposure which could mediate neurocognitive outcomes. This prospective study leverages a 50+ year follow-up of a subset of the Child Health and Development Studies (CHDS) birth cohort that was designed to investigate developmental origins of health disparities; N ~400 offspring were examined in midlife with prior follow-up in childhood and adolescence. This study has available maternal, prenatal, and offspring midlife biospecimens as well as life-course social factors, anthropometry, and health status, and is 40% black. We will use high resolution GC-MS and LC-MS to measure exposures and the metabolome in both targeted and untargeted analysis. This is an efficient use of existing data and biospecimens; no new human data collection is required. Our transdisciplinary team (Epidemiology, Cohn; Metabolomics & Exposomics, Jones; Neurotoxicology, Richardson) has collaborated previously ensuring feasibility. Aim 1 will identify associations of prenatal exposures (pesticides, PAHs, and novel exposures) with midlife 50-year AD-related outcomes and altered metabolic response. Aim 2 will identify potentially actionable biomarkers by identifying associations between altered midlife metabolome and AD-related outcomes. Aim 3 will determine if adolescent cognition: a) is associated with the prenatal exposome, b) predicts midlife AD- related outcomes, c) mediates associations of the prenatal exposome with midlife AD-related outcomes. This unique study can discover mechanisms that link the early life environment to AD and identify midlife interventions that may mitigate early life insults.
