Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genetics
• Microbiology

Background:

• The apolipoprotein E4 (APOE4) genotype is the leading genetic risk factor for Alzheimer's disease (AD).
• APOE4 carriers experience premature declines in brain metabolism and gut microbiome diversity, increasing AD susceptibility.
• Sex-based differences in AD risk suggest a need to investigate genotype- and sex-specific effects of interventions.

Purpose of the Study:

• To determine if a ketogenic diet (KD) can reverse early metabolic and microbiome deficits in young, asymptomatic APOE4 mice.
• To assess sex-based differences in response to KD in APOE3 and APOE4 mice.
• To identify microbial and metabolic correlates of AD risk.

Main Methods:

• Female and male APOE3 and APOE4 mice were fed a control or ketogenic diet for 16 weeks.
• Brain metabolomics and fecal metagenomic sequencing were performed.
• Microbiome diversity (alpha and beta) and metabolite-microbe correlations were analyzed.

Main Results:

• The KD restored brain metabolism and increased gut microbiome diversity in APOE4 female mice.
• These beneficial effects were not observed in APOE3 mice or APOE4 male mice.
• Specific gut microbes, including Bacteroides intestinalis and Lactobacillus species, correlated with key metabolic pathways.

Conclusions:

• A ketogenic diet effectively ameliorates AD-related metabolic and microbiome changes in APOE4 female mice.
• The therapeutic potential of KD for AD risk mitigation may be sex-specific.
• Gut microbes and their associated metabolites represent promising targets for AD intervention and screening.