Genetic susceptibility to Lewy body disease and the distribution of Lewy pathology
- 1Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
Abstract
Genome-wide association studies of Parkinsons 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 Parkinsons Genetics Program (GP2) and the National Institutes of Health NeuroBioBank, and estimated genetic correlation with clinically diagnosed Alzheimers 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 Alzheimers disease co-pathology, age at death and sex.
Under a neuropathological case definition, five established loci reached genome-wide significance: APOE {varepsilon}4 (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' Parkinsons disease variant. Among 1,216 cases diagnosed during life with Parkinsons disease, with or without dementia, the 3' variant was the lead SNCA signal, and the APOE {varepsilon}4 effect was attenuated (OR 1.57, 95% CI 1.37-1.81). Genetic correlation with Alzheimers disease (0.33, P = 0.02) persisted after excluding the APOE region (0.31, P = 0.03). Within cases, APOE {varepsilon}4 was the only susceptibility locus associated with neocortical involvement (OR 1.70, 95% CI 1.45-1.98; P = 2.5 x 10-11), including among 666 GP2 cases without significant Alzheimers disease co-pathology (OR 1.76, 95% CI 1.18-2.63; P = 0.005). Each additional {varepsilon}4 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 {varepsilon}4 was also associated with neocortical involvement, independently of measured Alzheimers disease co-pathology, suggesting that it influences not only whether Lewy pathology develops but how far it extends.
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BibTeX
@misc{wu2026genetic,
title = {{Genetic susceptibility to Lewy body disease and the distribution of Lewy pathology}},
author = {L. Y. Wu and J. W. Taylor and M. Valori and T. Georgiades and T. du Toit and A.-L. Gil-Martinez and E. J. Stafford and K. Levine and Z.-H. Fang and C. Blauwendraat and A. B. Singleton and S. W. Scholz and B. J. Traynor and J. Hardy and P. Chinnery and R. Cain and C. Troakes and D. Gveric and C. McLean and S. Love and A. King and A. C. Robinson and F. Roncaroli and C. Shepherd and G. Halliday and L. Parkkinen and C. M. Morris and J. Attems and C. Smith and G. E. Serrano and T. G. Beach and S. Gentleman and T. T. Warner and T. Lashley and Z. Jaunmuktane and O. A. Ross and D. W. Dickson and L. Pihlstrom and R. Real and H. R. Morris and Global Parkinson's Genetics Program (GP},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.21.26366146},
url = {https://www.medrxiv.org/content/10.64898/2026.10.21.26366146v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Genetic susceptibility to Lewy body disease and the distribution of Lewy pathology
AU - L. Y. Wu
AU - J. W. Taylor
AU - M. Valori
AU - T. Georgiades
AU - T. du Toit
AU - A.-L. Gil-Martinez
AU - E. J. Stafford
AU - K. Levine
AU - Z.-H. Fang
AU - C. Blauwendraat
AU - A. B. Singleton
AU - S. W. Scholz
AU - B. J. Traynor
AU - J. Hardy
AU - P. Chinnery
AU - R. Cain
AU - C. Troakes
AU - D. Gveric
AU - C. McLean
AU - S. Love
AU - A. King
AU - A. C. Robinson
AU - F. Roncaroli
AU - C. Shepherd
AU - G. Halliday
AU - L. Parkkinen
AU - C. M. Morris
AU - J. Attems
AU - C. Smith
AU - G. E. Serrano
AU - T. G. Beach
AU - S. Gentleman
AU - T. T. Warner
AU - T. Lashley
AU - Z. Jaunmuktane
AU - O. A. Ross
AU - D. W. Dickson
AU - L. Pihlstrom
AU - R. Real
AU - H. R. Morris
AU - Global Parkinson's Genetics Program (GP
PY - 2026
DA - 2026/10/21
PB - medRxiv
DO - 10.64898/2026.10.21.26366146
UR - https://www.medrxiv.org/content/10.64898/2026.10.21.26366146v1
AB - Genome-wide association studies of Parkinsons 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 Parkinsons Genetics Program (GP2) and the National Institutes of Health NeuroBioBank, and estimated genetic correlation with clinically diagnosed Alzheimers 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 Alzheimers disease co-pathology, age at death and sex. Under a neuropathological case definition, five established loci reached genome-wide significance: APOE {varepsilon}4 (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' Parkinsons disease variant. Among 1,216 cases diagnosed during life with Parkinsons disease, with or without dementia, the 3' variant was the lead SNCA signal, and the APOE {varepsilon}4 effect was attenuated (OR 1.57, 95% CI 1.37-1.81). Genetic correlation with Alzheimers disease (0.33, P = 0.02) persisted after excluding the APOE region (0.31, P = 0.03). Within cases, APOE {varepsilon}4 was the only susceptibility locus associated with neocortical involvement (OR 1.70, 95% CI 1.45-1.98; P = 2.5 x 10-11), including among 666 GP2 cases without significant Alzheimers disease co-pathology (OR 1.76, 95% CI 1.18-2.63; P = 0.005). Each additional {varepsilon}4 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 {varepsilon}4 was also associated with neocortical involvement, independently of measured Alzheimers disease co-pathology, suggesting that it influences not only whether Lewy pathology develops but how far it extends.
ER -