The gut microbiota, Alzheimer’s disease, and the central nervous system

Researchers at the University of Nevada, Las Vegas, have identified an association between Alzheimer’s disease and specific groups of microorganisms in the gut. In a paper published in Scientific reports Entitled “Genetic Correlations Between Alzheimer’s Disease and Gut Microbiome,” the researchers explain how they narrowed the research to half a dozen disease-associated microbes, with one associated with risk the most important.

The study authors point to a growing body of research indicating that perturbations in the normal proportions and lower diversity of the gut microbiota are associated with neurodegenerative diseases via neuroinflammatory processes across the gut-brain microbiota axis. Previous studies have also indicated that Alzheimer’s patients have reduced microbiome diversity.

The researchers used polygenic risk scores, an assessment of risk based on known genetic associations with disease, from 119 microbiomes of each individual from a discovery sample of 1,278 cases with 1,293 controls. They found that 20 out of 119 genders were significantly associated with a diagnosis of Alzheimer’s disease.

Of the 20 significant species, six were identified as at-risk species and 14 as potentially protective for the diagnosis of Alzheimer’s disease.

The dangerous genera included Alistipes and Bacteroides from the Bacteroidetes phylum, Lachnospira and Veillonella from the Firmicutes division, and Collinsella from the Actinobacteria and Sutterella from the Pseudomonadota phyla. Bacteroides were the most important species associated with risk.

For protective species, 11 out of 14 were from the phylum Firmicutes, two were from Actinobacteria, and one was from Bacteroidetes (Prevotella 9). The most important protective genus was Intestinibacter.

Those findings alone would make for an interesting research paper, but the researchers seemed more interested in good science, so they challenged their findings with a follow-up analysis.

A second database from GenADA, a Canadian multisite collaborative study of Alzheimer’s patients, was used. The same techniques were used to find associations between microorganisms in 799 cases with 778 controls. Data from this replication study differed from the first in some areas, but where the two trials overlapped were four significant associations that indicated the most likely culprit.

APOE4

Apolipoprotein E (APOE) is the cholesterol and lipid carrier protein of the central nervous system. Among the three major human transcripts of the protein, APOE2, APOE3 and APOE4, APOE4 gene expression is one of the most important risk factors associated with the development of late-onset Alzheimer’s disease.

When the researchers looked deeper into the microbial overlapping associations with Alzheimer’s disease, they found that these patients had another interesting thing in common. Polygenic risk scores for the four microorganism species had significant associations with copy-specific APOE rs429358-C genotype.

Collinsella from the superfamily Actinobacteria was identified as a risk factor for Alzheimer’s disease in both discovery and replication samples and had the most significant associations with the APOE genotype at rs429358-C.

The paper notes that previous studies have found that Collinsella is associated with higher serum levels of total cholesterol and low-density lipoprotein (LDL) cholesterol in healthy adults, which the researchers speculate may be related to interactions between Collinsella and APOE.

The authors conclude that future research is needed to explore the relationship between Collinsella, lipid metabolism and inflammatory signals to clarify how their interaction affects Alzheimer’s and other diseases.

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