Do APOE Variants Affect Alzheimer's Disease Risk via the Gut Microbiome?

Variations in the APOE gene correlate with risk of Alzheimer's disease. This has long been thought to relate to mechanisms promoting amyloid-β aggregation, given the centrality of the amyloid cascade hypothesis to Alzheimer's research. Scientists have recently provided evidence to suggest that increased inflammatory behavior of the innate immune cells called microglia in the brain is an important mechanism linking APOE variant and Alzheimer's risk, however. So this is not a completely settled area of research.

Separately, evidence exists for Alzheimer's disease patients to tend to exhibit a distinct and more harmful gut microbiome. The microbial populations of the intestinal tract are demonstrated to shift in relative abundance with advancing age. Microbes that provoke inflammation and tissue dysfunction grow in number, while beneficial microbes that produce needed metabolites are lost. Immune dysfunction is thought to be an important cause of this change, as the immune system is responsible for gardening the gut microbiome, but equally it is also the case that chronic inflammatory stimuli are to some degree a cause of immune aging.

The immune systems of the body and brain are somewhat distinct: different cell populations, different environments separated by the blood-brain barrier. They are connected by inflammatory signaling and a very limited degree of passage of cells back and forth, however. If one is roused to chronic inflammation, the other will be as well. Thus one might consider that microglial inflammation and an inflammatory gut microbiome are both manifestations of the same issue. It is interesting that this issue, however it might arise, whatever the ordering of cause and effect, appears to be affected by subtle changes in the behavior of APOE. What is clear, both here and in a great deal of other research relating to age-related neurodegenerative conditions, is that chronic inflammation is something to be avoided.

Genetic correlations between Alzheimer's disease and gut microbiome genera

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 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.

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