Age-associated pathology promotes APOE genotype and sex specific effects on the compositional and functional profile of the gut microbiome in the EFAD transgenic mice.

There are 5.7 million Americans diagnosed with Alzheimer disease, a fatal neurodegenerative disease with no cure and few palliative treatments. The gut microbiome consists of gastrointestinal bacteria involved in the digestion and production of critical metabolites for the host, a role disrupted in Alzheimer disease patients. Thus, the gut microbiome would be potential Alzheimer disease therapeutic target, as the reestablishment of a healthy gut microbiome has reportedly improved cognition in humans. However, the development of effective gut microbiome-targeted therapeutics is stalled, likely by the unclear effects of the universal biological variables of Alzheimer disease risk on the bacterial composition and metabolic function of the gut microbiome. To study the interactions among UBVs on the gut microbiome, we utilized the EFAD transgenic mice , a mouse model that exhibits an age-dependent Alzheimer disease phenotype. Bacteria from 8M EFAD fecal samples were isolated and identified using shotgun metagenomic sequencing. shotgun metagenomic sequencing was performed to identify metabolic pathways affected by the interactive effects of APOE genotype and sex. The effects of age-associated pathology were evaluated across 4M and 8M EFAD fecal samples using 16S rRNA gene amplicon sequencing. Bacterial diversity in the 8M EFAD gut microbiome were substantially affected by sex, predominantly driven by the greater relative abundance of Lactobacilli species in the femaleE4FAD gut microbiome compared to male E4FAD. Gene enrichment analysis demonstrated that the femaleEFAD gut microbiome was associated with greater bacterial infection mechanisms and synthesis of polyunsaturated fatty acids. Moreover, the female E4FAD gut microbiome exhibited a potential deficit in essential amino acids and short chain fatty acids, along with greater infective and invasive mechanisms. In comparison to 4M cohorts, the 8M EFAD gut microbiome exhibited significantly greater bacterial diversity, yet 8M E4FAD gut microbiome had greater relative abundance of pathogenic bacteria.