The EPND cohort: study design and CSF proteomics across Alzheimer’s disease, dementia with Lewy bodies, and Parkinson’s disease

The development of treatments for Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and Parkinson’s disease (PD) is hampered by the scarce understanding of disease-specific and shared pathophysiological mechanisms. Cohorts covering AD, DLB, and PD with multiple, harmonized in vivo biomarkers of both established pathology and broader molecular processes are scarce, limiting comparisons across diseases. Therefore, we set up the European Platform for Neurodegenerative Diseases (EPND) cohort. Here, we describe its design and methods. Additionally, we explore disease-specific and shared cerebrospinal fluid (CSF) proteomic changes across diseases. To build the EPND cohort, participants with AD, DLB, PD, or controls were selected from ten European cohorts. Samples were centrally analysed. Amyloid-β (Aβ) 42, Aβ40, phosphorylated tau (​​p-tau) 181, and neurofilament light were measured in CSF and plasma, and total α-synuclein in CSF (all using Elecsys). Complement assays were performed in CSF (Milliplex) and plasma (SVAR), and proteomics panels (Olink Explore 3072, SomaScan 7k) were measured in CSF. Cohort data on demographics, clinical information, cognition, rating scales, lifestyle, genetics, and key imaging measures were centrally harmonized. Using this cohort, we explored CSF proteins ( n = 1617) uniquely and commonly dysregulated across diseases, measured by Olink proximity extension assays. Data were analyzed by linear regression adjusted for age, sex, and mean CSF protein level (average z-scored level of all highly detected Olink proteins). P-values were FDR-corrected. 353 participants were included (age 67.1 [SD 9.2], 133 [38%] female) in the EPND cohort, of which 151 with AD, 67 with DLB, 75 with PD, 57 controls, and 3 with other diagnoses. Sample analyses and data harmonization generated five datasets, which can be requested​ through the EPND Catalogue for research reuse. Exploratory proteomic analyses in a subset (325 participants) revealed CSF proteins specifically dysregulated in AD ( n = 9), DLB ( n = 1), or PD ( n = 2), as well as proteins similarly dysregulated across AD and DLB ( n = 10) and across DLB and PD ( n = 4), but not across AD and PD. The EPND cohort represents a valuable resource for neurodegenerative disease research, covering AD, DLB, and PD with centrally measured targeted and high-plex biomarkers. Available for research reuse via the EPND Catalogue, this cohort supports collaborative studies across neurodegenerative diseases. Current and future results will provide insights into disease-specific and common pathophysiological mechanisms and inform trial designs.