Developing Topics.

Abstract

APOE*2 and APOE*4 are respectively the strongest protective and risk-increasing genetic variants for late-onset Alzheimer's disease (AD), making APOE status highly relevant towards clinical trial design and AD research broadly. The associations of APOE genotypes with AD are importantly modulated by age, sex, race, ethnicity, and ancestry, but these associations remain unclear, particularly in historically understudied non-white samples. The study overview is shown in Figure.1. Various case-control, family-based, and longitudinal AD genetic cohorts were available through public repositories and underwent extensive genotype and phenotype quality control. These cohorts contributed data for Non-Hispanic Whites (NHW), Non-Hispanic Blacks (NHB), and Hispanics (HISP). Global ancestry was determined using SNPweights v2.1. Case-control logistic regression models evaluated the AD risk associations of APOE*2 dosage, APOE*4 dosage, and APOE genotype, with regard to APOE*33 as the reference, while adjusting for sex, array/batch/center, and global European, African, and Amerindian ancestry. Different stratified analyses, interaction models, and race/ethnicity heterogeneity tests were evaluated. APOE associations in East-Asians (EAS) were obtained through meta-analyses of published AD genetic studies, given the relative paucity of EAS in publicly available genetic cohorts. Compared to prior literature, we made several novel observations (Figure.2). Notably, the associations of APOE genotypes with AD risk were least pronounced in HISP, which was not explained by global ancestry. Further, not just APOE*4, but also APOE*2 followed a reduced association strength with AD risk according to the pattern of EAS > NHW > NHB > HISP (with the exception of APOE*2 in EAS, which showed no significant association). The sex-by-age-specific association of APOE*34 in NHW, which was shown to be stronger in women, was reproduced here at ages 60-70 years, and additionally replicated in NHB and HISP. There were no other significant sex-by-APOE interactions. Merited by recent advances in AD genetic cohorts, we provide the largest-to-date overview of APOE's associations with AD risk across important biological and demographic strata. We expect these insights to be critical to guide AD research and clinical trial design. With increased diversity and phenotype harmonization efforts in AD genetics, future extensions on this work are expected to provide additional insights.