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Background  Alzheimer’s disease (AD) is a fatal neurodegenerative disease.  APOE4  is the greatest genetic risk factor for AD, increasing risk up to 15-fold compared to the common  APOE3.  Importantly, female (♀)  APOE4  carriers have a greater risk for developing AD and an increased rate of cognitive decline compared to male ( ♂ )  APOE4  carriers. While recent evidence demonstrates that AD,  APOE  genotype, and sex affect the gut microbiome (GM), how  APOE  genotype and sex interact to affect the GM in AD remains unknown.    Methods  This study analyzes the GM of 4-month (4 M) ♂ and ♀ E3FAD and E4FAD mice, transgenic mice that overproduce amyloid-β 42 (Aβ42) and express human  APOE3   +/+   or  APOE4   +/+  . 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 across  APOE,  sex and stratified by  APOE +  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 of  APOE +  sex. Mann-Whitney tests and machine-learning algorithms identified differentially abundant taxa associated with  APOE  + sex.    Results  Significant differences in the EFAD GM were associated with  APOE  genotype and sex. Stratification by  APOE  + sex revealed that  APOE -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 genera  Prevotella  and  Ruminococcus  was significantly higher in ♀E4FAD compared to ♀E3FAD, while the relative abundance of  Sutterella  was 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.    Conclusions  The results demonstrate that the 4 M EFAD GM is modulated by  APOE  + sex. Importantly, the effect of  APOE4  on 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 of  APOE  + sex on the GM in young AD transgenic mice, changes associated with the development of pathology remain to be defined.

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