Overlap of genetic risk for Lewy body and Alzheimer’s disease pathology

Abstract

AbstractBackgroundLewy body (LB) pathology is relatively understudied compared to Alzheimer’s disease (AD) pathology, and the genetic risk overlap between the two remains unclear. Chia et al. (2021) identified five genomic loci significantly associated with LB pathology in a genome‐wide association study (GWAS) of LB dementia cases and controls (N = 6,618), where 69% of cases and 15% of controls were pathologically confirmed. Here we gathered a largely distinct set of individuals (5.1% overlap) with genetic data and postmortem assessment for both AD and LB pathology (N = 6,002) to estimate the odds ratio (OR) for risk of sole AD pathology (AD+LB−), sole LB pathology (AD−LB+), and dual AD‐LB pathology (AD+LB+) for the five variants reported by Chia et al. We compared our results for APOE to ORs reported by Tsuang et al. (2013).MethodOur initial study population comprised 4,579 subjects from the National Alzheimer’s Coordinating Center and 1,423 from the Rush University Medical Center assessed for AD and LB pathology. We separately used criteria from Tsuang et al. and from Kaivola et al. (2021) to classify subjects as AD+LB+, AD+LB−, AD−LB+, or AD−LB−. We performed a GWAS for three phenotypic contrasts: each of AD+LB−, AD−LB+, and AD+LB+ against AD−LB−. We estimated ORs for the variants of interest.ResultWe found that rs769449 (APOE locus) was associated with AD+LB+ and AD+LB− at the genome‐wide significance level and nominally associated with AD−LB+, though with OR estimates lower than those reported by Tsuang et al. We obtained qualitatively similar results for rs6733839 (BIN1). The lead variants reported at the GBA, TMEM175, and SNCA‐AS1 loci (or proxies in high linkage disequilibrium) were not associated with a pathological phenotype, although an independent intronic variant of GBA was nominally associated with AD+LB+ and AD−LB+.ConclusionOur results suggest that APOE and BIN1 are associated with both AD and LB pathology, while GBA is associated with LB but not AD pathology. The ORs reported by Tsuang et al. for APOE‐associated risk for single and dual AD‐LB pathology may overestimate the true population values. Overall, AD and LB pathology share APOE and BIN1 as risk factors.