Murine Gut Microbiome Association With APOE Alleles

Abstract

<b>Background:</b> Since <i>APOE</i> alleles represent the most impactful genetic risk factors for Alzheimer's disease (AD), their differential mechanism(s) of action are under intense scrutiny. <i>APOE4</i> is robustly associated with increased AD risk compared to the neutral <i>APOE3</i> and protective <i>APOE2</i>. <i>APOE</i> alleles have also been associated with differential inflammation and gastrointestinal recovery after insult in human and murine studies, leading us to hypothesize that <i>APOE</i> alleles impact the gut microbiome. <b>Methods:</b> To assess this hypothesis, we compared 16S ribosomal RNA gene amplicon-based microbiome profiles in a cohort of mice that were homozygous for <i>APOE2, APOE3, or APOE4</i>, and included both males and females as well as carriers and non-carriers of five familial AD (5xFAD) mutations. Fecal samples were analyzed from mice at 4 and 6 months of age. <i>APOE</i> genotype, as well as sex and 5xFAD status, was then tested for influence on alpha diversity (Shannon H index) and beta diversity (principal coordinate analyses and PERMANOVA). A Random Forest analysis was used to identify features that predicted <i>APOE</i>, sex and 5xFAD status. <b>Results:</b> The richness and evenness (alpha diversity) of the fecal microbiome was not robustly associated with <i>APOE</i> genotype, 5xFAD status or sex. In contrast, microbial community composition (beta-diversity) was consistently and strongly associated with <i>APOE</i> genotype. The association between beta-diversity and sex or 5xFAD status was less consistent and more modest. Comparison of the differences underlying <i>APOE</i> effects showed that the relative abundance of multiple bacterial taxa was significantly different as a function of APOE genotype. <b>Conclusions:</b> The structure of the gut microbiome was strongly and significantly associated with <i>APOE</i> alleles in this murine model. Further evaluation of these findings in humans, as well as studies evaluating the impact of the APOE-associated microbiota on AD-relevant phenotypes in murine models, will be necessary to determine if alterations in the gut microbiome represent a novel mechanism whereby <i>APOE</i> genotype impacts AD.