Genetic susceptibility to Lewy body disease and the distribution of Lewy pathology

Key numbers

• 2.5 x 10-11
• 95% CI 2.06-2.50
• 95% CI 2.01-3.28

Caveats

• Preprint; not yet peer reviewed.

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: APOE4 (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 APOE4 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, APOE4 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 e4 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 APOE4 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.

L. Y. Wu, J. W. Taylor, M. Valori, T. Georgiades, T. du Toit, A.-L. Gil-Martinez, E. J. Stafford, K. Levine, Z.-H. Fang, C. Blauwendraat, A. B. Singleton, S. W. Scholz, B. J. Traynor, J. Hardy, P. Chinnery, R. Cain, C. Troakes, D. Gveric, C. McLean, S. Love, A. King, A. C. Robinson, F. Roncaroli, C. Shepherd, G. Halliday, L. Parkkinen, C. M. Morris, J. Attems, C. Smith, G. E. Serrano, et al.

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• Citations0 (reference 20, via semantic-scholar, Oct 25, 2026, 06:17 UTC)

• Reviewed by heuristic-v10 on Oct 25, 2026, 06:17 UTC. Paper type: empirical.
• Categories: neurology
• BRIEF, No.6 in the Medicine edition of October 25, 2026.