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Genetic Risk Factor Links Alzheimer's Disease and Severe COVID-19

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Early in the COVID-19 pandemic, individuals with Alzheimer's disease were identified as being at increased risk of developing severe COVID-19.  "At first we thought that was because people with dementia were less likely to be able to adhere to physical distancing and mask wearing, or were exposed in their care institutions when there was a mass discharge from hospitals," Dr. David Strain, senior clinical lecturer at the University of Exeter said. "However, even after adjustment for these risk factors, those with even early dementia were still at a much higher risk."

A new study led by Dr. Dervis Salih and colleagues at University College London (UCL) suggests that an anti-viral gene, OAS1, might contribute to this observed association. The findings are published in the journal Brain.

OAS1 and Alzheimer's disease

The new study builds on previous work by the UCL team that reported a link between oligoadenylate synthetase 1 (OAS1) and Alzheimer's disease. The OAS1 gene is expressed in microglia, an immune cell that accounts for ~10–15% of the cells found in the brain. While the hallmark of Alzheimer's disease pathology is a build-up of amyloid plaques and TAU tangles in the brain, a growing body of research is demonstrating how the immune system – and in particular, inflammation – contributes.

What is the function of OAS1?

There are three forms of OAS proteins expressed in the human body: OAS1, OAS2 and OAS3. Each form is induced by the action of interferons, a group of cytokine proteins that activate a myriad of the immune system's defence mechanisms. Upon activation, OAS1 and OAS2 trigger the production of oligoadenylates and activate an enzyme known as RNase L, which digests RNA.

Variants and increased disease risk

Genetic variants exist between individuals and can lead to the production of a variant form of a protein. Under some circumstances, the protein variant may be faulty, or even absent; disrupting the typical function that is served within a cell or molecular pathway.

In a genome wide association study (GWAS) of 2,547 people – 50% of which had Alzheimer's disease – Salih and colleagues identified a variant of the OAS1 gene, known as rs1131454, that was linked to an increased likelihood of having the disease.

The researchers also found that four variants of the OAS1 gene associated with increased Alzheimer's disease susceptibility had been recently highlighted in COVID-19 research. The data suggested that possessing such variants resulted in an increased baseline risk of requiring intensive care treatment.

At the molecular level, the UCL researchers found that the four variants are all associated with a decreased expression of the OAS1 protein. Using immune cell models of COVID-19, they discovered that that when microglia were treated to have reduced expression of the OAS1 gene, a "cytokine storm" was initiated. Hyper-inflammation and cytokine storm syndrome (CSS) have been identified in many patients for which COVID-19 has proven fatal.

How can this research be applied?

Correlation does not prove causation, and that is a limitation associated with GWAS studies. Just because a certain variant is associated with an illness, it does not confirm that it causes the illness.

That being said, there are useful insights to be drawn from the new study, Strain said: "We do know that one of the key pathways in development of Alzheimer’s disease is inflammation within the brain tissue, and, as our understanding of the pandemic has grown, we have seen many other inflammatory conditions be highlighted as risk factors for poor outcomes, therefore the results are not overly surprising. It does add important information as to the pathogenesis of the more severe presentations of COVID and will hopefully be able to shed further light on potential treatment options or even personalised preventative medicine.”

The development of a method to analyze genetic variants in individuals that test positive for COVID-19 could be used to identify those at risk of requiring critical care, Salih said. "There is plenty more work to be done to get us there. Similarly, we hope that our research could feed into the development of a blood test to identify whether someone is at risk of developing Alzheimer’s before they show memory problems," he added.

Reference: Magusali N, Graham AC, Piers TM, et al. A genetic link between risk for Alzheimer’s disease and severe COVID-19 outcomes via the OAS1 gene. Brain. 2021;(awab337). doi: 10.1093/brain/awab337