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Background Genetic variants within the  APOE  locus may modulate Alzheimer’s disease (AD) risk independently or in conjunction with  APOE *2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of  APOE  pathophysiology and provide critical guidance for AD therapies aimed at  APOE . The  APOE  locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in  APOE *2/3/4 genotype quality. Here, we present a novel  APOE *2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1801 base pairs downstream of  APOE  and has been associated with a potential regulatory effect on  APOE . Methods We used thirty-two AD-related cohorts, with genetic data from various high-density single-nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD ( n  = 65,701). Primary analyses investigated AD risk in  APOE *4/4 carriers. Additional supporting analyses were performed in  APOE *3/4 and 3/3 strata. Outcomes were compared under two different  APOE *2/3/4 filtering approaches. Results Using more conventional  APOE *2/3/4 filtering criteria (approach 1), we showed that, when in-phase with  APOE *4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases the certainty of the  APOE *2/3/4 genotypes by applying more stringent criteria for concordance between the provided  APOE  genotype and imputed  APOE  genotype (approach 2), we observed that all significant effects were lost. Conclusions We showed that careful consideration of  APOE  genotype and appropriate sample filtering were crucial to robustly interrogate the role of the  APOE  locus on AD risk. Our study presents a novel  APOE  filtering approach and provides important guidelines for research into the  APOE  locus, as well as for elucidating genetic interaction effects with  APOE *2/3/4.

Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping