Project summary Parkinson's disease (PD) is a prevalent and progressive neurological disorder impacting more than 1 million Americans with a well-known prodromal period in which individuals experience non-specific symptoms before receiving a diagnosis. Critically, this diagnosis often occurs after widespread, irreversible neurodegeneration has already occurred. Those with PD then encounter an escalating burden of disability and symptom severity, resulting in substantial direct medical expenses related to pharmaceutical treatments, hospitalizations, and skilled nursing care. Despite the significant disease burden associated with PD, there is a scarcity of effective preventive measures or risk reduction strategies, and limited understanding of factors that influence the rate at which clinical PD develops or ‘phenoconversion’ for those with prodromal symptoms. Inflammation is an emerging key disease process contributing to PD risk and may play a key pathogenic role during the prodromal period. Conditions characterized by chronic inflammation and immune dysfunction, including several autoimmune disorders, are considered potential risk factors for PD; certain immune agents used to treat these conditions have also been associated with a lower risk of PD, offering a novel approach to reduce PD risk by targeting immune processes. However, the results of existing are inconsistent, potentially due to inadequate control for confounding or bias related to reverse causation; few have also assessed the impact of immune factors on the rate of phenoconversion to clinical PD. The goals of this proposal are to evaluate whether long- term exposure to immune therapies is a strategy to reduce PD risk and phenoconversion rates. For this study, we will leverage genetic and risk factor information and detailed follow-up available as a part of three large-scale biobanks in which we will consider comprehensive array of therapeutic agents used to treat a range of autoimmune diseases (AIDs) as they relate to PD. Specifically, we will utilize the well-characterized effects of genetic variation in influencing the expression or function of individual AID therapeutic targets as instruments to help to understand the downstream effects of AID treatment on PD risk and phenoconversion. This epidemiologic framework will be embedded within a comprehensive bioinformatic pipeline in which extensive differential expression and epigenetic remodeling-based analyses at the single-cell level will further refine and characterize novel immune-associated therapeutic targets in the context of PD. Our central hypothesis is that inflammatory mechanisms contribute to both PD and AIDs, and that certain therapies approved to target immune processes in AIDs may be novel strategies to mitigate PD risk and phenoconversion. The collective results of this project will (1) help to improve risk stratification; (2) unravel new mechanisms contributing to disease risk and progression in PD’s early stages; and...