PROJECT SUMMARY/ABSTRACT One of the most common Alzheimer’s Disease Related Dementias (ADRD) is Lewy body dementia. This umbrella term comprises two clinically distinct ADRDs: Parkinson’s disease dementia (PD-dementia) and dementia with Lewy bodies (DLB). There has been a growing interest in the genetic bases of DLB, however, PD-dementia has not yet been studied using large-scale genetic analyses. Nevertheless, it has been shown that dysfunction of the endolysosomal pathway plays a key role in Alzheimer’s disease and ADRDs. This involvement, however, is not fully understood and the exact failure points for each disease have yet to be identified. Thus, there is a gap in knowledge regarding the specific molecular mechanisms underlying each disease. This application aims to identify genetic variability that modulates risk for PD-dementia and its neuropathological features, determining the overlap with other ADRDs and the immediate downstream effects on endolysosomal function. The hypothesis, based on preliminary data, is that PD-dementia has a measurable and unique genetic architecture and that its integration with current knowledge of the molecular bases of other ADRDs, will improve the understanding of the lysosome as a central pathological hub in neurodegenerative diseases. This hypothesis will be tested by pursuing three specific aims: 1) identify candidate risk-modulating variants for PD-dementia; 2) determine neuropathological correlates of genetic risk; and 3) identify downstream effects of high-risk variability in neurons and glial cells across ADRDs. One cohort of clinically diagnosed PD- dementia cases and one cohort of neuropathological diagnosed cases will be tested under a GWAS framework to identify risk modulating variants in a two-stage study. The neuropathological cases will also undergo whole- genome sequencing to identify common and rare genetic variability, allowing for the first genomics study with gold-standard characterization of neuropathology in a large cohort of PD-dementia cases. Last, the immediate cell-specific effects of disease-specific risk profile will be determined by performing single-cell RNA-seq in brain tissue from individuals with the highest polygenic risk for each of these two ADRDs and for AD. The proposed research focuses for the first time on PD-dementia cases, as a strict diagnosis, taking advantage of large-scale unbiased genetic analyses and integrating that with related disorders. The proposed research is significant because it will provide a composite genetic profile specific for this Lewy body dementia. The proposed study design has the potential to identify targets that are common to different forms of ADRDs, as well as novel, personalized, disease-specific targets; this proposal is a direct response to the National Alzheimer's Project Act (NAPA) Public Law 111-375, NAPA 2012 2013, and NAPA 2016.