(P23-026-23) Ketogenic Diet Rescues Gut Microbiome and Cortical Metabolites in Apolipoprotein E Mice With Sex-Specific Responses

Objectives: Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for Alzheimer’s disease (AD), with females have a higher risk than males. Studies show, asymptomatic APOE4 carriers have imbalanced gut microbiome compared to non-carriers (e.g., APOE3); females may have different gut microbiota composition than males, which may increase the risk for AD pathology. Studies have shown that ketogenic diet (KD) may be effective to restore dysbiosis and mitigate AD risk; however, it remains unclear whether the response to KD varies by APOE, genotype, and sex. The present study aims to address this gap in knowledge.

Methods: At three months of age, C57BL/6 transgenic human E3 and E4 male and female mice (n=6-12), were fed either a control or ketogenic diet ad libitum for 16 weeks. Fecal samples were collected for shotgun metagenomic sequencing. Nontargeted metabolomics analysis was performed on the right hemisphere of each mouse brain. Plasma was collected for short chain fatty acid (SCFA) analysis. Two-way and three-way ANOVA tests were performed followed by Tukey’s multiple comparisons test.

Results: Regardless of APOE genotype or sex, we found that mice fed KD had significant changes in beta (β)-diversity, increases in phylum Firmicutes and decreases in Bacteroidetes, and thus the Firmicutes: Bacteroidetes (F:B) ratio. The increases of Firmicutes are associated with increases health promoting bacteria such as Lactobacillus johnsonii and Lactobacillus reuteri. The microbiome changes are associated with increased SCFA acetate in plasma.

When stratifying with sex, APOE4 female (E4-F) mice had different β-diversity compared with APOE4 male groups, but the difference was normalized by KD. Similarly, compared with APOE3 females, APOE3 and APOE4 males, E4-F mice had lower brain metabolites related to mitochondrial TCA cycle and neurotransmitters, e.g., citrate, fumarate, malate, GABA, and glutamine, which were restored by KD.

Conclusions: KD can increase F:B ratio, SCFA, and probiotics-related bacteria, which may be critical to mitigate AD, regardless of APOE genotype or sex. Specifically, for E4-F mice who had higher dysbiosis and lower essential metabolites compared with other three groups. Taken together, KD may be very helpful to mitigate AD risk for E4-F by protecting gut microbiome and brain metabolism at an early stage.

Funding Sources: NIH/NIA grant RF1AG062480