OVERALL ABSTRACT/SUMMARY The mission of this Penn PO1 Center on “Mechanisms underlying heterogeneity of cognitive outcome in synucleinopathy” is to understand why the same underlying core pathology – inclusions of alpha-synuclein (aSyn) – varies so widely in the pace and pattern of spread within the brain, resulting in dramatically divergent clinical trajectories. The Lewy body disorders (LBD) – namely, dementia with Lewy bodies (DLB), Parkinson’s disease (PD), and Alzheimer’s disease with Lewy bodies (LBD+AD) – share the core feature of neuronal aSyn inclusions. However, patients manifest very differently from one another, with differences in cognition playing a vital role with respect to patient quality of life and cost to the healthcare system. Because the LBD affect so many, with no FDA-approved disease-modifying therapies, they constitute one of the most important Alzheimer’s Disease Related Dementias (ADRD) affecting the world today. This PO1 Center hypothesizes that several key features play fundamental roles in determining whether a given LBD individual might develop dementia from the outset, after a few years, after many decades, or not at all. These features are: (1) the interplay of aSyn with - amyloid plaques and tau neurofibrillary tangles, (2) the conformation of aSyn, (3) host genomics and proteomics, and (4) the locus/entry point of early pathology. We test this hypothesis in four synergistic Research Projects. Project I investigates the role of concomitant -amyloid and tau pathology in governing patterns of aSyn spread in human postmortem brain. Project II characterizes human brain-derived aSyn strains with cryo-ET and cell biological techniques. Project III leverages genomic and biomarker data to derive candidate molecular players, then manipulates these genes/proteins in neurons to understand their role in the uptake of fibrillar aSyn, development of aSyn pathology, and cell-to-cell transmission of aSyn pathology. Project IV extends our investigations of host factors to mouse models, testing the role of genetic background, route of aSyn exposure, and type of aSyn strain in modulating in vivo pathological aSyn spread. All four research projects focus on mechanisms, grounded in human data, and they are supported by four Cores that (1) serve Administrative functions, (2) recruit Clinical patients, (3) provide biosample Resources to Research Projects and to external investigators, and (4) manage Data for Research Projects and sharing to external investigators. Thus, the Penn PO1 Center seeks to discover and develop new therapeutic strategies to delay or prevent dementia in the LBD.