Alzheimer's Disease (AD), AD-related dementias (ADRD) and other neurodegenerative diseases such as Parkinson’s disease (PD) exhibit pathogenic gene-environment interactions (GxE) with synergistic effects of exposure to an environmental chemical/pathogen and genotype. Recent progress in next- generation sequencing has expedited the discovery of genetic risk factors associated with Alzheimer's disease, AD-related dementias and Parkinson’s disease. Yet, identified genetic factors only account for a fraction of patients, and not all patients with the identified genetic risks develop disease. This is exasperated for AD/ADRD/PD as it is convoluted with many covariates over a person’s lifetime. To elucidate the contribution of GxE to disease we propose an approach based on the principles of latent-persistent effects of environmental neurotoxicants; and the developmental origins of adult disease hypothesis. We seek to test the hypothesis that persistent neurotoxicity is due to exposures altering self-perpetuating homeostatic processes that give the resiliency and perpetuity to the adverse toxicological processes by either genetic and/or epigenetic means. Specifically, we will collect samples from same-sex siblings in northern Indiana that phenotypically differ in AD/ADRD/PD relevant cognitive and motor dysfunction phenotypes; reprogram blood cells into human induced pluripotent stem cells (hiPSCs); differentiate them into cortical and midbrain lineages; and characterize their vulnerability to induction of a persistent neurotoxic state caused by neurodevelopmental exposures to environmental hazard/toxicants relevant to this region and history. We expect to identify a persistent neurotoxic state with a conserved response shared across individuals at the level of the genetic/epigenetic pathways evoked. 'Age-related signaling' networks have been defined as central pathways regulating healthy lifespan and aging and are thus expected as a shared network feature conferred by GxE risks. Our innovative approach will leverage single-cell genomics approaches and pathway analysis to identify mechanisms activated by subject-specific GxE to cause a persistent neurotoxic state with only a small subject size and low FDR. The following aims will test our hypothesis and validate the shared signaling networks: Aim 1: Identify subject by toxicant interactions contributing to persistent neurotoxicity using human cells derived from paired Alzheimer's disease, AD-related dementias and Parkinson’s disease and healthy cohort with comparable exposure histories; Aim 2: Identify genetic pathways associated with establishing a persistent neurotoxic state via single-cell genomics and bioinformatic comparisons to population level data; and Aim 3: Validate the genetic pathways of GxE induction of persistent neurotoxicity with in vivo and in vitro models. This work seeks to understand how past environmental exposures influence AD/ADRD/PD disease risk and incidence by utilizing an interd...