PROJECT SUMMARY/ABSTRACT (CLINICAL CORE) The Clinical Core of the proposed NIA P01 at the University of Pennsylvania (UPenn) Perelman School of Medicine will be crucial to accomplishing the goals of all Projects and other Cores of this multidisciplinary research program. The proposed UPenn NIA P01 will focus on priorities that address Alzheimer’s disease (AD) and related dementias (ADRD) in topic areas of multiple etiology dementias, such as Lewy body (LB) disorders (LBD), including Parkinson’s disease (PD) dementia (PDD) and dementia with Lewy bodies (DLB). During life, LBD patients manifest very differently from one another, with DLB patients demonstrating dementia from disease onset, whereas PD patients initially show motor symptoms predominantly. Moreover, although some PD patients do go on to develop cognitive dementia, others do not, and even among those who develop PDD, the pace varies widely – with cognitive symptoms developing over months to decades. The overall goals of this new UPenn P01 is to understand why the same underlying core pathology – inclusions of aSyn – varies so widely in the pace and pattern of spread within the brain, resulting in dramatically different clinical trajectories. We focus on mechanisms, with the goal of intervening in these pathological processes. This mechanistic focus, grounded in human data, is key to preventing the cognitive decline and dementia that currently affect so many. The aims for the Clinical Core are to: (1) recruit, assess and retain research participants with LBD for P01Projects I-IV; (2) collaborate with the Resource Core for biomarker/biofluid and tissue collection from existing and new Clinical Core LBD participants, and to assess them longitudinally antemortem for as long as possible to optimize clinical-pathological correlations; and (3) collaborate with Data Management and Statistics Core to contribute high-quality clinical and biomarker data to the UPenn Integrated NeuroDegenerative Disease Database (INDD) and facilitate sharing of clinical and biomarker data within and outside of UPenn with new and longstanding internal, national and international collaborators.