The effects of sex and APOE genotype on the gut microbiome in EFAD transgenic mice

While the gut microbiome (GM), the collective genome of bacteria in the gastrointestinal tract, is primarily studied in metabolism and immune defense, the GM may also serve as a diagnostic tool and therapeutic target in neurological disorders, including Alzheimer's disease (AD). While age is the greatest risk factor for AD, the e4allele of APOE is the greatest genetic risk factor, increasing risk up to 15‐fold compared to APOE3 , the common genotype. APOE4 is associated with the accelerated accumulation of the peptide amyloid‐b(Ab), which can aggregate to form both amyloid plaques and small soluble aggregates or oligomeric Ab (oAb), the latter considered a proximal neurotoxin. Importantly, among APOE4 carriers, females have an increased AD risk, rate of cognitive loss and accumulation of Ab42 compared to males. Although the GM of individuals with AD exhibit specific microbial differences compared to healthy controls, a greater understanding of how age, APOE genotype and sex contribute to the altered GM in AD may help determine the diagnostic potential of the GM composition. To study the interactions among these AD risk factors, we developed the EFAD‐transgenic mice, which express the human APOE genotypes and over‐express human Ab42. Thus, our hypothesis is that APOE genotype and sex interact to modulate the GM composition in EFAD mice . Fecal samples from 4 month (M) ♂ and ♀ E3FAD and E4FAD mice were sequenced and compared. The Shannon H index, a measure of species richness and diversity, identified a negative correlation between diversity and severity of AD pathology in the 4M EFAD cohorts of mice: ♂E4FAD > ♀E4FAD and ♀E3FAD > ♀E4FAD. Analysis of similarities (ANOSIM) demonstrated significant differences in the GM in E3FAD vs E4FAD across different taxonomic levels (operational taxonomic unit/OTU, Genus, and Family). Comparison across sex within APOE genotype revealed a significant difference between ♂E3FAD vs ♂E4FAD and ♀E3FAD vs ♀E4FAD at all taxonomic levels. Additionally, there is a significant effect for ♂E4FAD vs ♀E4FAD, though only at the OTU level. Further, heatmap analysis demonstrates clustering of ♀E4FAD samples based on 29 OTUs. Therefore, the synergistic effect of APOE4 and female sex on AD risk is exhibited by the GM, observed by the stratification of the EFAD cohorts. This study is the first step in defining the composition of the GM as a function APOE genotype and sex modulation of AD pathology. Support or Funding Information LaDu lab funding includes institutional funds from the University of Illinois College of Medicine, the Bridge to the Doctorate Fellowship, and the Honor's College Undergraduate Research Award at the University of Illinois at Chicago. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .