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

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, 14 415 variants near APOE (±500 kilobase) for 18 795 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 < .05 divided by the number of independent tests per model were considered statistically significant. Results: Among the 18 795 individuals in the study, 9704 were affected by AD and 9066 were control individuals; the median age at onset/evaluation was 76 (interquartile range, 70-82) years; and 11 167 were female (59.4%). Associations with AD were found for rs2075650 (odds ratio [OR], 2.59; 95% CI, 2.45-2.75; P = 3.19 × 10-228) and rs4420638 (OR, 2.77; 95% CI, 2.62-2.94; P = 2.99 × 10-254) without APOE adjustment. Although rs2075650 was nominally associated with AD among the ε4 homozygotes (OR, 1.33; 95% CI, 1.00-1.77; P = .047), the association between rs4420638 and AD was eliminated by APOE adjustment (model 2 OR, 1.06 [95% CI, 0.96-1.18; P = .24]; model 3 OR, 1.13 [95% CI, 0.95-1.34; P = .18]; model 4 OR, 0.90 [95% CI, 0.56-1.45; P = .66]). There was a significant association between rs192879175 and AD among ε3 homozygotes (OR, 0.50; 95% CI, 0.37-0.68; P = 8.30 × 10-6). Conclusions and Relevance: The results of this genetic association study suggest that ε2/ε3/ε4 alleles are not the only variants in the APOE region that are associated with AD risk. Additional work with independent data is needed to replicate these results.