The E4 allele of the APOE gene is the largest genetic risk factor for late-onset Alzheimer’s disease (AD). As such, significant effort has been dedicated to understanding the different roles and mechanisms by which APOE4 confers risk and drives AD. However, until fairly recently, much of this work was focused on mechanisms within the brain. APOE has roles and can be produced outside of the brain; however, this has prompted some to begin to explore how peripheral roles of APOE4 contribute to AD risk. Recent studies have shown the importance of the gut microbiome, the collection of living microbes that reside in the gut, in mediating the risk of several neurodegenerative conditions, including AD. Some studies have shown that APOE4 carriers have a gut microbiome that looks different from non-carriers, raising the intriguing possibility that APOE4 might have an impact on the brain via the gut.
Dr. Bendlin is a leading expert on the role of the gut microbiome in AD, and here aims to investigate the role of APOE4 on the relationship between the gut microbiome and AD. She and her team have previously shown that even well before any onset of AD, human APOE4 carriers have a gut microbiome composition that differs compared to non-carriers. Additionally, her team identified specific metabolites, small molecules generated as part of the gut microbiome’s metabolic activity, that were associated with changes in amyloid, tau, and neurodegeneration biomarkers consistent with AD. Specifically, Dr. Bendlin hypothesizes that the most relevant changes in APOE4 carriers are related to lipid and bile acid metabolism. Bile acids are produced in the liver, which also produces APOE; they are important in the breakdown of fats and lipids in the gut and also act as potent signals for other metabolic pathways. Here, she aims to test this hypothesis and build on her strong preliminary studies.
The project consists of three primary experimental aims, all of which will leverage samples from a cohort of over 500 research participants enrolled in longitudinal studies at the University of Wisconsin. The first aim will build on the initial findings showing distinct microbiome composition in APOE4 carriers by conducting further sequencing experiments. They will also examine the functional differences caused by these compositional shifts using advanced sequencing analysis techniques. The second aim will then build upon the data linking microbiome changes to changes in AD biomarkers, including both imaging and fluid biomarkers related to amyloid, tau, and neurodegeneration. They will also examine the impact of different microbiome compositions on changes in cognition over an extended period. The final aim focuses on the pathways related to bile acid and lipid metabolism. They will utilize advanced metabolomic and lipidomic approaches to assess exactly how, and to what extent, relevant pathways are influenced by APOE4, as well as to determine which pathways are most relevant to AD-related changes.
Overall, this project investigates the intersection between one of the most significant risk genes for AD, APOE4, and the gut microbiome to understand how they interact and contribute to AD risk and progression in a clinical setting. The project is positioned to provide insights into how the gut microbiome may influence AD biomarkers and identify relevant metabolic pathways that could be viable therapeutic targets in future studies.
