Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Genome-wide association studies of Parkinson’s disease and dementia with Lewy bodies largely rely on clinical diagnoses, which can misclassify cases and cannot characterise the anatomical distribution of Lewy pathology. Autopsy cohorts allow identification of variants associated both with developing Lewy body disease and with the neocortical extent of its pathology. We meta-analysed genome-wide data from 2,661 individuals of European ancestry with autopsy-confirmed Lewy body disease and 12,068 controls (2,124 autopsy-confirmed) from the Global Parkinson’s Genetics Program (GP2) and the National Institutes of Health NeuroBioBank, and estimated genetic correlation with clinically diagnosed Alzheimer’s disease. In 2,309 cases from the GP2 and the Mayo Clinic Jacksonville Brain Bank, we compared neocortical (n = 1,362) with brainstem or limbic (n = 947) Lewy pathology, adjusting for Alzheimer’s disease co-pathology, age at death and sex. Under a neuropathological case definition, five established loci reached genome-wide significance: APOE ε4 (OR 2.27, 95% CI 2.06-2.50), GBA1 E326K (OR 2.57, 95% CI 2.01-3.28), SNCA (OR 1.35, 95% CI 1.23-1.48; TMEM175 p.M393T (OR 1.30, 95% CI 1.19-1.43), and HLA class II (OR 0.69, 95% CI 0.61-0.79). Lead associations differed by antemortem diagnosis. Across all cases, the SNCA association was indexed by a 5′ signal previously associated with dementia with Lewy bodies and rapid eye movement sleep behaviour disorder, rather than the canonical 3′ Parkinson’s disease variant. Among 1,216 cases diagnosed during life with Parkinson’s disease, with or without dementia, the 3′ variant was the lead SNCA signal, and the APOE ε4 effect was attenuated (OR 1.57, 95% CI 1.37-1.81). Genetic correlation with Alzheimer’s disease (0.33, P = 0.02) persisted after excluding the APOE region (0.31, P = 0.03). Within cases, APOE ε4 was the only susceptibility locus associated with neocortical involvement (OR 1.70, 95% CI 1.45-1.98; P = 2.5 × 10 −1 1 ), including among 666 GP2 cases without significant Alzheimer’s disease co-pathology (OR 1.76, 95% CI 1.18-2.63; P = 0.005). Each additional ε4 allele was also associated with a more advanced Lewy pathology stage (OR 1.76, 95% CI 1.50-2.06). Autopsy-confirmed Lewy body disease shares its major susceptibility loci with clinically defined disease. Of these, only APOE ε4 was also associated with neocortical involvement, independently of measured Alzheimer’s disease co-pathology, suggesting that it influences not only whether Lewy pathology develops but how far it extends.
Source: medRxiv
Authors: Lesley Y. Wu, Jared W. Taylor, Miko Valori, Tatiana Georgiades, Tessa du Toit, Ana-Luisa Gil-Martinez, Eleanor J. Stafford, Kristin Levine, Zih-Hua Fang, Cornelis Blauwendraat, Andrew B. Singleton, Sonja W. Scholz, Bryan J. Traynor, John Hardy, Patrick Chinnery, Richard Cain, Claire Troakes, Djordje Gveric, Catriona McLean, Seth Love, Andrew King, Andrew C. Robinson, Federico Roncaroli, Claire Shepherd, Glenda Halliday, Laura Parkkinen, Christopher M Morris, Johannes Attems, Colin Smith, Geidy E. Serrano, Thomas G. Beach, Steve Gentleman, Thomas T. Warner, Tammaryn Lashley, Zane Jaunmuktane, Owen A. Ross, Dennis W. Dickson, Lasse Pihlstrøm, Raquel Real, Huw R Morris, the Global Parkinson’s Genetics Program (GP2)
Institutions: UCL Queen Square Institute of Neurology, Data Tecnica International (United States), Oslo University Hospital, University of Oslo, UK Dementia Research Institute, Imperial College London, Stellenbosch University, German Center for Neurodegenerative Diseases, Coalition for Aligning Science, National Institutes of Health, Johns Hopkins University, Johns Hopkins Medicine, National Institute of Neurological Disorders and Stroke, National Institute on Aging, University College London, University of Cambridge, University of Bristol, King's College London, University of Manchester, UNSW Sydney, Neuroscience Research Australia, The University of Sydney, University of Oxford, NIHR Newcastle Biomedical Research Centre, Newcastle University, Innsbruck Medical University, Universität Innsbruck, University of Edinburgh, Banner Sun Health Research Institute, National Hospital for Neurology and Neurosurgery, Mayo Clinic, Mayo Clinic in Florida
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Michael J. Fox Foundation for Parkinson's Research, Arizona Department of Health Services, UK Research and Innovation, Alzheimer's Society, National Institute for Health and Care Research, Parkinson's UK, Arizona Biomedical Research Commission, National Institutes of Health, Medical Research Council, NIHR Newcastle Biomedical Research Centre, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke
Awards: G1576660248, Defining and diagnosing neurodegenerative Movement Disorders through integrated analysis of Genetics And neuroPathology (MD-GAP), G1783170366, G250893170, G2510966662, G2898431357, G3250808129, G3251040009, G3521153818, G3903239027, G554305069, G6030318873, G6099246109, G7836467104, G9000132673, Genetic characterization of atypical parkinsonism, G961669115
OpenAlex ID: W7223445787