Project Summary Lewy body dementia (LBD), a class of disorders comprising Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), features aggressive cognitive and neuropsychiatric decline without cure or effective mitigating therapies. Driving the clinical challenges surrounding LBD is a poor understanding of the pathophysiology underlying its clinical deterioration and a desperate lack of diagnostic, progressive, and therapeutic biomarkers. Neuropathological evidence suggests that corticolimbic synucleinopathy is closely linked to the aggressive dementia of LBD and that effective biomarkers of cognitive and neuropsychiatric decline would necessarily reflect this corticolimbic dysfunction. Thus, our central hypothesis is that the corticolimbic LBD brain features regional and disease-specific alterations in neuronal and non-neuronal pathways reflected as unique protein signatures in CSF and plasma. To investigate this hypothesis, we will apply an integrated network-based proteomic pipeline across brain, cerebrospinal fluid (CSF), and plasma to identify LBD biofluid signatures anchored in corticolimbic pathophysiology. Our preliminary experience with this pipeline suggests it is a powerful promoter of multiplexed biomarker assays reflective of diverse brain-based dysfunction, including neuronal, glial, and endothelial pathophysiology. In addition to these proteomic experiments, we will also establish an Emory LBD registry under the Parkinson’s Disease Biomarker Program (PDBP) and utilize its clinical and biospecimen data to fuel proteomic validation studies and promote future LBD research. Our specific aims include 1) building a longitudinal PDBP registry for LBD, 2) defining the corticolimbic network proteome of LBD, 3) performing brain-biofluid proteomic integration to identify promising biofluid markers, and 4) longitudinal biofluid validation using targeted proteomic strategies. In addition to biospecimens collected in Aim 1, we will supplement these experiments using existing brain and biofluid samples housed in Emory Goizueta Alzheimer’s Disease Research Center biorepositories. Ultimately, our efforts to identify molecular signatures of cognitive and neuropsychiatric decline in LBD promise to discover novel biomarkers to enhance early diagnosis, disease monitoring, and gauging therapeutic response. Furthermore, such markers can serve as a necessary gateway to effective drug therapies for this devastating spectrum of neurodegenerative diseases.