Objective: To identify genetic risk factors associated with the distribution of Lewy body (LB) and Alzheimer’s disease (AD) co-pathology in the Lewy body disease (LBD) brain.

Background: Parkinson’s Disease (PD), PD dementia (PDD) and Dementia with Lewy bodies (DLB), collectively named as Lewy body diseases (LBD), are characterized pathologically by alpha-synuclein aggregates forming Lewy bodies and Lewy neurites. Cognitive and neuropsychiatric complications observed in LBDs correlate with the development of cortical Lewy body pathology. LB pathology can be divided into subcortical, limbic and neocortical stages.

Method: We studied a large series of Brain Bank LBD cases to define the genetic drivers of regional LB pathology. We included 1208 pathologically defined LBD cases with summary pathological scores together with genotyping using the Illumina Neurobooster array (NBA) and whole genome sequencing with 150 base-pair paired-end sequencing with 30x coverage generated in the Global Parkinson’s Genetic Program (gp2.org).  We ran a case-case GWAS, comparing cases who developed cortical LB pathology  vs cases without. We further meta-analyzed with the Mayo clinic cohort (n =  960). We also applied an ordinal GWAS model using Braak NFT stages, CERAD and Thal phases to the same dataset.

Results: We found rs769449 tagging APOE e4 to be the most significant genetic risk associated with cortical LB (OR = 2.07, 95% CI = 1.75 – 2.45, P-value = 2.515e-17). APOE e4 was also significantly associated with more severe AD co-pathology.

Conclusion: Our results suggest APOE e4 drives both Lewy body and Alzheimer’s co-pathology in the LBD brain. Further analysis of common and rare risk variants is underway to provide new insights into the pathogenesis of these diseases.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-determinants-of-the-progression-of-lewy-body-pathology/