Association of Uncommon, Noncoding Variants in the APOE Region with Risk of Alzheimer Disease in Adults of European Ancestry

Abstract

Importance: The ϵ2 and ϵ4 alleles of the apolipoprotein E (APOE) gene are associated with Alzheimer disease (AD) risk. Although nearby genetic variants have also been shown to be associated with AD, including rs2075650 in the TOMM40 gene and rs4420638 near the APOC1 gene, it is unknown whether these associations are independent of the ϵ2 and ϵ4 alleles. Objective: To assess whether variants near APOE are associated with AD independently of the ϵ2/ϵ3/ϵ4 genotype. Design, Setting, and Participants: In this genetic association study of the Alzheimer's Disease Genetics Consortium imputed genotype at data, 14415 variants near APOE (±500 kilobase) for 18795 individuals with European ancestry were tested for association with AD using 4 logistic mixed models adjusting for sex, cohort, population structure, and relatedness. Model 1 had no APOE adjustment, and model 2 adjusted for the count of ϵ2 and ϵ4 alleles. Model 3 was restricted to ϵ3 homozygotes, and model 4 was restricted to ϵ4 homozygotes. Data were downloaded from May 31, 2018, to June 3, 2018, and analyzed from November 1, 2018, to June 24, 2020. Main Outcomes and Measures: Alzheimer disease affectation status was defined by clinicians using standard National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer Disease and Related Disorders Association criteria. Association was evaluated using Score tests; results with P