Alzheimer’s Disease and COVID-19 Share a Genetic Risk Factor

Dawn O'Shea

October 13, 2021

A study led by University College London (UCL) has found a link between genetic risk for Alzheimer's disease and susceptibility to critical illness with COVID-19. The findings, published in Brain, could open the door for new targets for drug development.

For the study, the research team sought to build on their previous work, which found evidence from a large data set of human genomes to suggest a link between the anti-viral oligoadenylate synthetase 1 (OAS1) gene and Alzheimer’s disease which is mediated through its enrichment in transcriptional networks expressed by microglia.

The same OAS1 locus has recently been linked to an increased risk of severe COVID-19 outcomes. The single nucleotide polymorphisms rs1131454(A) and rs4766676(T) are associated with Alzheimer's disease, and rs10735079(A) and rs6489867(T) are associated with severe COVID-19, where the risk alleles are linked with decreased OAS1 expression.

Analysing single-cell RNA-sequencing data of myeloid cells from Alzheimer's disease and COVID-19 patients, the team have identified co-expression networks containing interferon (IFN)-responsive genes, including OAS1, which are significantly upregulated with age and both diseases.

In human-induced pluripotent stem cell-derived microglia with lowered OAS1 expression, the study shows exaggerated production of tumour necrosis factor (TNF)-α with IFN-γ stimulation, indicating OAS1 is required to limit the pro-inflammatory response of myeloid cells.

Collectively, the data support a link between genetic risk for Alzheimer's disease and susceptibility to critical illness with COVID-19, centred on OAS1. The findings could have potential implications for future treatments for Alzheimer's disease and COVID-19, and the development of biomarkers to track disease progression.

Lead author Dr Dervis Salih from UCL Queen Square Institute of Neurology and the UK Dementia Research Institute, said: "While Alzheimer’s is primarily characterised by harmful build-up of amyloid protein and tangles in the brain, there is also extensive inflammation in the brain that highlights the importance of the immune system in Alzheimer’s. We have found that some of the same immune system changes can occur in both Alzheimer’s disease and Covid-19."

"In patients with severe Covid-19 infection there can also be inflammatory changes in the brain. Here we have identified a gene that can contribute to an exaggerated immune response to increase risks of both Alzheimer’s and Covid-19."

"If we could develop a simple way of testing for these genetic variants when someone tests positive for Covid-19, then it might be possible to identify who is at greater risk of needing critical care, but 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."

"We are also continuing to research what happens once this immune network has been activated in response to an infection like Covid-19, to see whether it leads to any lasting effects or vulnerabilities, or if understanding the brain’s immune response to Covid-19, involving the OAS1 gene, may help to explain some of the neurological effects of Covid-19."

This article originally appeared on Univadis, part of the Medscape Professional Network.

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