Genetic risk of Alzheimer’s disease is partially mediated by gut bacteria composition

Abstract

Abstract Recent studies indicated that many genes which are associated with Alzheimer’s disease (AD) risk are also associated with the composition of gut microbiota, suggesting a potentially causal relationship. Other studies suggested that certain gut microbiota may lead to increased risk for neurodegeneration through their role in the microbiota-gut-brain axis. The three-way relationship between expression of AD risk genes, gut bacteria composition, and AD risk remained unclear. This study aimed to investigate the potential causal relationships between gene expression, gut bacteria, and AD. We performed multivariable Mendelian Randomization (MVMR) analyses using summary statistics from genome-wide association studies (GWAS) for Alzheimer’s disease (N = 455K), gut bacteria composition (N = 18K), and gene expression (N = 2.6K) in cortex tissue. We found evidence that at least 22 of the 36 genes may have causal effects on late-onset Alzheimer’s Disease (LOAD) risk which are at least partially mediated by gut bacteria. Alternatively, 14 genes have no evidence of effect mediation by gut bacteria. We also found evidence that levels of Acidaminococcaceae, Clostridiaceae, Lachnospiraceae, Ruminococcaceae, Verrucomicrobiaceae, and Victivallaceae may lead to a direct increase or decrease in LOAD risk. These findings may provide targets for preventative treatment and generate further studies on the mechanism of the gut-brain axis.