Genetic correlations between gut microbiome genera, Alzheimer’s disease diagnosis, and APOE genotypes: a polygenic risk score study

Abstract Background: A growing body of evidence suggests that dysbiosis of the human gut microbiota is associated with neurodegenerative diseases like Alzheimer’s disease (AD) via neuroinflammatory processes across the microbiota-gut-brain axis (MGBA). The gut microbiota affects brain health through the secretion of toxins and short-chain fatty acids, which modulates gut permeability and numerous immune functions. Observational studies indicate that AD patients have reduced microbiome diversity, which could contribute to the pathogenesis of the disease. Uncovering the genetic basis of microbial abundance and its effect on AD could suggest lifestyle changes that may reduce an individual’s risk for the disease. Methods: Using the largest genome-wide association study (GWAS) of gut microbiota genera from the MiBioGen consortium, we conducted the polygenic risk score (PRS) analysis with the “best-fit” model implemented in PRSice-2 and determine the genetic correlation between 119 genera and AD in a discovery sample (case/control: 1,278/1,293). We then replicated our findings in an independent sample (case/control: 799/778) and further confirmed the correlation with meta-analysis. Finally, we conducted a linear regression analysis to assess the correlation between the PRSs for the significant genera and the APOE genotypes. Results: In the discovery sample, 20 gut microbiota genera were initially identified as genetically associated with AD case/control status. Three genera ( Eubacterium fissicatena as a protective factor , Collinsella, and Veillonella as a risk factor) were replicated in the replication sample. The meta-analysis confirmed that ten genera have a significant correlation with AD, four of which were significantly associated with the APOE rs429358 risk allele in a direction consistent with their protective/risk designation in AD association. Notably, the proinflammatory genus Collinsella, identified as a risk factor for AD, was positively correlated with the APOE rs429358 risk allele in both samples. Conclusion: Host genetic factors influencing the abundance of ten genera are significantly associated with AD, suggesting that these genera may serve as biomarkers and targets for AD treatment and intervention. Our results highlight that proinflammatory gut microbiota might promote AD development through interaction with APOE . Larger datasets and functional studies are required to understand their causal relationships.