Genetic correlations between Alzheimer's disease and gut microbiome genera

Abstract

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. 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. Using the largest genome-wide association study of gut microbiota genera from the MiBioGen consortium, we used polygenic risk score (PRS) analyses with the "best-fit" model implemented in PRSice-2 and determined the genetic correlation between 119 genera and AD in a discovery sample (ADc12 case/control: 1278/1293). To confirm the results from the discovery sample, we next repeated the PRS analysis in a replication sample (GenADA case/control: 799/778) and then performed a meta-analysis with the PRS results from both samples. Finally, we conducted a linear regression analysis to assess the correlation between the PRSs for the significant genera and the APOE genotypes. In the discovery sample, 20 gut microbiota genera were initially identified as genetically associated with AD case/control status. Of these 20, three genera (Eubacterium fissicatena as a protective factor, Collinsella, and Veillonella as a risk factor) were independently significant in the replication sample. Meta-analysis with discovery and replication samples confirmed that ten genera had 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. Overall, the 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.

Figure 1

Study design flowchart. In the PRS analysis, “Base” data is used to provide effect sizes for SNPs shared with individuals in the “Target” data. Using PRSice-2, 20 genera were found to be significantly genetically associated with AD diagnosis in the discovery sample. Three genera were validated in the replication sample, and ten were confirmed by a meta-analysis from discovery and replicate samples. Linear regression analyses were used to determine the genetic correlation between the PRSs for ten significant genera and APOE genotyping. Three genera were identified as genetically correlated with APOE rs429358 risk allele C.

Figure 2

Forest plots of ten genera significantly associated with AD from meta-analysis. (A) The genetically predicted abundance of six genera showed significant association (p < 0.00042) with AD diagnosis as a protective factor with ORs < 1.0. (B) Conversely, four genera showed significant association with AD as a risk factor with ORs > 1.0. OR (95%CI): Odds ratio of the respective genus with the lower and upper 95% confidence intervals.

Figure 3

Normalized PRSs for ten significant genera between AD cases and controls in the discovery sample. (A) PRSs for six genera were relatively lower in AD cases than controls (p < 0.05), suggesting they might be a protective factor for AD. (B) PRSs for four genera were relatively higher in AD cases vs. controls (p < 0.05), suggesting they were likely be a risk factor for AD. Wilcoxon Rank Sum test was applied to generate p values. X-axis: Diagnosis (AD cases/controls). Y-axis: z-score normalized PRSs for each of the ten significant genera.

Figure 4

Genetic association between PRSs for Collinsella and APOE rs429358 genotype in the discovery sample. Individuals in the discovery sample were separated by their genotype at the APOE SNP rs429358. Those with the genotype of TC and CC had higher PRSs for genetically predicted Collinsella abundance than those with the TT genotype.