Synergistic effects of APOE and sex on the gut microbiome of young EFAD transgenic mice

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a fatal neurodegenerative disease.APOE4is the greatest genetic risk factor for AD, increasing risk up to 15-fold compared to the commonAPOE3.Importantly, female (♀)APOE4carriers have a greater risk for developing AD and an increased rate of cognitive decline compared to male (♂)APOE4carriers. While recent evidence demonstrates that AD,APOEgenotype, and sex affect the gut microbiome (GM), howAPOEgenotype and sex interact to affect the GM in AD remains unknown.MethodsThis study analyzes the GM of 4-month (4 M) ♂ and ♀ E3FAD and E4FAD mice, transgenic mice that overproduce amyloid-β 42 (Aβ42) and express humanAPOE3+/+orAPOE4+/+. Fecal microbiotas were analyzed using high-throughput sequencing of 16S ribosomal RNA gene amplicons and clustered into operational taxonomic units (OTU). Microbial diversity of the EFAD GM was compared acrossAPOE,sex and stratified byAPOE + sex, resulting in 4-cohorts (♂E3FAD, ♀E3FAD, ♂E4FAD and ♀E4FAD). Permutational multivariate analysis of variance (PERMANOVA) evaluated differences in bacterial communities between cohorts and the effects ofAPOE + sex. Mann-Whitney tests and machine-learning algorithms identified differentially abundant taxa associated withAPOE + sex.ResultsSignificant differences in the EFAD GM were associated withAPOEgenotype and sex. Stratification byAPOE + sex revealed thatAPOE-associated differences were exhibited in ♂EFAD and ♀EFAD mice, and sex-associated differences were exhibited in E3FAD and E4FAD mice. Specifically, the relative abundance of bacteria from the generaPrevotellaandRuminococcuswas significantly higher in ♀E4FAD compared to ♀E3FAD, while the relative abundance ofSutterellawas significantly higher in ♂E4FAD compared to ♂E3FAD. Based on 29 OTUs identified by the machine-learning algorithms, heatmap analysis revealed significant clustering of ♀E4FAD separate from other cohorts.ConclusionsThe results demonstrate that the 4 M EFAD GM is modulated byAPOE + sex. Importantly, the effect ofAPOE4on the EFAD GM is modulated by sex, a pattern similar to the greater AD pathology associated with ♀E4FAD. While this study demonstrates the importance of interactive effects ofAPOE + sex on the GM in young AD transgenic mice, changes associated with the development of pathology remain to be defined.