A LANDMARK genome-wide association study of 1,483 Lewy body disease (LBD) cases has identified APOE ε4 as the strongest genetic driver of neuropathological severity, independently linking it to Alzheimer’s-like pathology and Lewy body spread in these neurodegenerative disorders.
Lewy body disease – encompassing Parkinson’s disease and dementia with Lewy bodies – remains poorly understood genetically despite its global health burden. While prior studies focused on candidate genes, this first large-scale GWAS of neuropathological features in LBD examined 11 outcomes across 980 discovery and 503 replication cases. The findings redefine our understanding of how genetic factors shape disease progression and pathology in LBD, particularly the unexpected centrality of APOE ε4 beyond its traditional Alzheimer’s associations.
Researchers analysed neuropathological data from postmortem brains, including Braak neurofibrillary tangle stages, Lewy body counts across five regions, and substantia nigra neuronal loss. APOE ε4 showed genome-wide significance for increased Braak NFT severity (discovery OR=3.07, p=2.34×10⁻³²; replication OR=2.30, p=2.70×10⁻¹¹), Thal amyloid phase (discovery OR=3.57, p=3.28×10⁻²⁹; replication OR=3.17, p=6.39×10⁻¹⁸), and LBD subtype classification (discovery OR=1.78, p=9.85×10⁻⁹; replication OR=2.68, p=3.85×10⁻¹⁰). Strikingly, APOE ε4 maintained strong associations with LBD subtype even in cases with minimal Alzheimer’s pathology (discovery OR=2.47, p=0.007; replication OR=3.60, p=0.006). Three novel loci – LINC01581/MCTP2, TLE3, and GRIN2A/ATF7IP2 – showed tentative links to Lewy body distribution but failed replication. Neuronal loss in the substantia nigra showed no significant genetic associations.
These results revolutionise clinical understanding of LBD progression, suggesting APOE ε4 drives pathology through mechanisms distinct from its Alzheimer’s role, potentially via neuroinflammation or blood-brain barrier dysfunction. For neurologists and pathologists, APOE genotyping could become critical for prognostic stratification, particularly in early-stage LBD cases. Future research must prioritise meta-analyses to validate secondary genetic signals and functional studies elucidating APOE’s synucleinopathy mechanisms. Therapeutic development should explore targeting APOE ε4-related pathways, while biomarker studies need to assess how these genetic associations translate to antemortem diagnostics. Multicentre collaborations will be essential to expand diversity beyond the current European-ancestry focus and uncover ancestry-specific genetic architectures.
Reference
Valentino RR et al. Genome-wide association study of neuropathological features in Lewy body disease. Brain. 2025;awaf105.
