The Surprising Impact of APOE Alleles on Gut Microbiome: Does Altering the Microbiome Reduce AD Risk?

This application focuses on the interface between inflammation, the microbiome and Alzheimer’s disease (AD) genetics to identify and test a novel hypothesis for AD risk. That inflammation modulates AD risk has been firmly established by recent genetic studies wherein AD-associated polymorphisms in TREM2 and CD33 appear to regulate microglial activation. Microglial maturation and function is also modulated by short chain fatty acids (SCFA)s which are primarily generated as resistant starch metabolites by the gut microbiome. The microbiome is emerging as a regulator of the human condition and is itself modulated by the immune system, probiotics and diet. Whether the gut microbiome modulates AD is unclear, although antibiotic treatment or a germfree environment reduces AD-related phenotypes in murine models. Here, we propose a novel link between AD genetics and the gut microbiome. This study resulted from a serendipitous meeting at an APOE conference with Richard Guerrant, who described his studies showing that gut health in humans and mice is associated with APOE genotype; when humans in a third world environment suffer from diarrheal outbreaks, APOE4 carriers have less severe disease and better outcomes, relative to APOE3 individuals. Similar findings were found in an APOE targeted replacement (TR) murine model wherein APOE4 was associated with improved responses to gastrointestinal infection and undernourishment, compared to APOE3. The possibility that APOE modulates the gut microbiome is also supported by a recent report showing microbiome variation between wild-type and APOE deficient mice. Considering these findings, we propose the global hypothesis that APOE alleles modulate the gut microbiome and that this action contributes to APOE allelic effects on AD risk. As a corollary, we further hypothesize that altering the microbiome to be more similar to the APOE2 microbiome will reduce AD risk. To evaluate this scientific premise, we submit the following Specific Aims: 1) Test the hypothesis that the gut microbiome is associated with APOE genotype in a murine model, 2) Test the hypothesis that the human gut microbiome is associated with APOE genotype, and 3) Test the hypothesis that the APOE-associated gut microbiomes modulate AD-related phenotypes in a murine model. In summary, this proposal is based upon highly novel and compelling preliminary results that APOE alleles influence the gut microbiome. If successful, this interdisciplinary proposal will yield novel insights regarding AD genetics, the gut microbiome and prebiotic approaches to reduce AD risk.