Association between Human Leukocyte Antigen Alleles and Neuropathological Outcomes in Lewy Body Disease.

Abstract

Lewy body disease (LBD) is a complex neurodegenerative disorder characterized by the accumulation of misfolded α-synuclein in the brain. Neuroinflammation has long been implicated in LBD pathogenesis, and recent genetic studies in Parkinson's disease (a clinical manifestation of LBD) have shown consistent association with the human leukocyte antigen (HLA) gene complex. Here, we assessed whether variation in HLA alleles influences neuropathological burden in a neuropathologically-defined series of LBD cases. We conducted a comprehensive analysis of HLA allelic variants in a cohort of 539 LBD cases of European descent from the Mayo Clinic brain bank. High-resolution whole-genome sequencing was used, and the HLA alleles of each sample were called using the HLA*LA tool and assessed for association with neuropathological outcomes. Our analysis identified 1 significant (P < 3.43 × 10^-5) and 4 suggestive (P < 0.001) associations between certain HLA alleles and specific neuropathological outcomes in LBD, suggesting a potential role for HLA-mediated immune mechanisms in disease progression and subtype differentiation. Specifically, HLA-DPB1*06:01 was significantly associated with lower Lewy body counts in the parahippocampal gyrus (P = 3.30 × 10^-5), with weaker and suggestive associations observed in the middle frontal (P = 1.80 × 10^-4) and inferior parietal gyrus (P = 6.33 × 10^-4). Additionally, although only suggestive, HLA-DRB1*11:01 correlated with a lower Thal amyloid phase (P = 1.56 x 10^-4), and HLA-B*15:01 correlated with an increased risk of diffuse LBD (P = 7.58 x 10^-4). This study provides a detailed evaluation of the relationship between HLA alleles and LBD pathology, highlighting the importance of immune-related genetic factors in the etiology of LBD. ANN NEUROL 2026;99:492-501.