Project Abstract It is widely believed that complex gene-environment interactions underlie the development and progression of AD. Exposure to synthetic environmental toxicants has been extensively linked to AD. Despite the association between environmental exposure and AD risk, the mechanisms underlying toxicant-induced neurodegenerative processes are poorly understood. Using targeted or candidate approaches, epidemiologic studies have identified compounds strongly associated with dementia and AD. However, new and emerging chemicals are constantly entering our ecosystem. For these reasons, it is important to take an unbiased approach in determining which chemicals are associated with disease. Recently, we used unbiased LC and GC-based HRMS to determine toxicants negatively associated with IQ levels in serum from participants of the Reference Ability Neural Network (RANN) study. The comprehensive cognitive assessments in RANN assess many of the features associated with Alzheimer’s disease and related dementias (ADRD). Through this approach, we identified these top 5 compounds: fonofos (organophosphate pesticide), PCB 183 (industrial polychlorinated biphenyl), lindane (organochlorine pesticide), 1,2-dibromo-3-chloropropane (DBCP) (soil fumigant/nemacide), and cis-permethrin (pyrethroid pesticide). These compounds represent a multitude of chemical classes, highlighting the importance of untargeted analysis in identifying possible novel contributors to disease. Despite their seemingly disparate nature, these data suggest that different chemicals might converge on similar molecular pathways contributing to cognitive decline. Based on a previous targeted study that demonstrated that a metabolite of the organochlorine pesticide DDT was elevated in AD patient plasma, we characterized DDT-induced neurodegenerative outcomes and metabolomic alterations in C. elegans. We found DDT exposure exacerbates neurodegenerative phenotypes caused by expression of the AD-associated human tau protein, reducing growth, altering swim behavior, exacerbating protein misfolding, and causing metabolome-wide alterations. Using the technical toolkit and computational pipelines we already have in place under the parent R01, we seek to characterize AD-like outcomes in C. elegans exposed to these newly identified compounds. We hypothesize that exposure to these toxicants will 1) result in AD-like neurodegenerative phenotypes and 2) dysregulate similar metabolomic pathways. Specific Aim 1: Characterize AD-associated behavioral and pathologic outcomes in C. elegans expressing AD-related mutant tau exposed to putative cognition-impairing toxicants. Specific Aim 2: Discover metabolomic pathways altered by putative cognition-impairing toxicants. Successful completion of these aims will provide molecular characterization of the mechanisms by which environmental toxicants contribute to neurodegeneration.