Evidence from a large data set of human genomes suggests a link between the antiviral OAS1 gene and Alzheimer’s disease

Elderly patient holding hand in hospital bed

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 antiviral 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 patients with Alzheimer’s disease and COVID-19, the team 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 showed exaggerated production of tumour necrosis factor-α with IFN-γ stimulation, indicating that 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 the 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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