PROJECT I: ABSTRACT The overall objective of this project is to develop predictive models of alpha-synuclein (aSyn) propagation in the human brain in Lewy body dementia (LBD) patients to define biologically meaningful subgroups of LBD and guide the development of prognostic biomarkers to track the propagation of aSyn. There are shared clinical and biological underpinnings within the spectrum of Parkinson’s disease (PD), PD with dementia (PDD), and Dementia with Lewy bodies (DLB), collectively referred to as LBD due to the shared pathological substrate of underlying alpha-synuclein aSyn inclusions in the central nervous system. Our previous histopathological and autopsy-confirmed biomarker work finds that Alzheimer’s disease (AD) tau co-pathology associates with more rapid decline and specific features of language and memory dysfunction in LBD. Thus, biological classification of LBD based on the presence or absence of AD tau co-pathology (i.e. LBD+AD vs LBD-AD) is more clinically informative than classic LBD phenotypes (i.e. PDD vs DLB) alone. While aSyn pathology propagation within the nervous system is an important driver of neurodegeneration, there is limited data on specific cellular vulnerabilities to aSyn in the human brain and how these relate to heterogenous cognitive symptoms of dementia in LBD. Network science is a powerful approach to study relationships between the complex hierarchical structure of the human brain and cognitive symptoms, but thus far, has largely been limited to study of in vivo imaging of relatively small groups of PD or DLB patients without autopsy or biomarker confirmation needed to account for AD co-pathology and to study cellular aSyn pathologic contributions to network breakdown on the macroscopic level. Here, we propose two specific aims to uniquely apply network science to our large autopsy cohort using graph theoretical analyses to analyze gold-standard digital histopathology metrics postmortem and integrate these cellular models on the microscopic and mesoscopic levels with antemortem autopsy/biomarker- confirmed in vivo MRI data to comprehensively examine the cellular substrates of neurocognitive degeneration and cognitive impairment in LBD. This project integrates seamlessly into the overall aims and objectives of this program project grant by providing critical human clinical and pathological data to guide future imaging biomarkers sensitive to tracking aSyn and tau propagation and identify neuronal populations selectively vulnerable to aSyn and tau. Moreover, this project informs the mechanistic work in Projects II-IV, while insights gained from Projects II-IV enhance the study of human brain tissue and in vivo MRI and clinical data here.