University Of College London Study Shows That Both The OAS1 Gene Is A Risk Factor For Both Alzheimer's Disease and COVID-19 Severity
OAS1 Gene and COVID-19
: A new study by researchers from University of College London (UCL) has found that the OAS1 gene is a risk factor for bot the development of Alzheimer's Disease as well as COVID-19 severity.
The study team had previously reported that oligoadenylate synthetase 1 (OAS1
) contributed to the risk of Alzheimer’s disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1
within microglia was not known.
By utilizing genotyping from 1313 individuals with sporadic Alzheimer’s disease and 1234 control individuals, the stud team confirmed that the OAS1
variant, rs1131454, is associated with increased risk for Alzheimer’s disease. The same OAS1
locus has been recently associated with severe coronavirus disease 2019 (COVID-19) outcomes, linking risk for both diseases. 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
By analyzing single-cell RNA-sequencing data of myeloid cells from Alzheimer’s disease and COVID-19 patients, the study 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 findings showed exaggerated production of TNF-α with IFN-γ stimulation, indicating OAS1
is required to limit the pro-inflammatory response of myeloid cells.
The study findings support a link between genetic risk for Alzheimer’s disease and susceptibility to critical illness with COVID-19 centred on OAS1
, a finding with potential implications for future treatments of Alzheimer’s disease and COVID-19, and development of biomarkers to track disease progression.
The study findings were published in the peer reviewed journal: Brain https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awab337/6382473?searchresult=1
The study team estimates that one genetic variant of the OAS1 gene increases the risk of Alzheimer's disease by about 3-6% in the population as a whole, while related variants on the same gene increase the likelihood of severe COVID-19 outcomes.
The OAS1 Gene-COVID-19
study findings could open the door for new targets for drug development or tracking disease progression in either disease, and suggest that treatments developed could be used for both conditions.
The study findings also have potential benefits for other related infectious
conditions and dementias.
Dr Dervis Salih, lead author from UCL Queen Square Institute of Neurology and UK Dementia Research Institute at UCL told Thailand Medical News, "While Alzheimer's is primarily characterized 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.”
Dr Salih further added, "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."
The study team sought to build on their previous work, which found evidence from a large dataset of human genomes, to suggest a link between the OAS1 gene and Alzheimer's disease. https://pubmed.ncbi.nlm.nih.gov/32274467/
It should be noted that the OAS1 gene is expressed in microglia, a type of immune cell that constitutes around 10% of all cells found within the brain.
Studying the gene's link to Alzheimer's further, the team sequenced genetic data from 2,547 individuals, half of whom had Alzheimer's disease.
Significantly, the study team found that individuals with a particular variation, called rs1131454, of the OAS1 gene were more likely to have Alzheimer's disease, increasing carriers' baseline risk of Alzheimer's by an estimated 11-22%.
Interestingly the new variant identified is common, as just over half of Europeans are believed to carry it, and it has a bigger impact on Alzheimer's risk than several known risk genes.
This study findings add OAS1, an anti-viral gene, to a list of dozens of genes now known to affect a person's risk of developing Alzheimer's disease.
The study team also investigated four variants on the OAS1 gene, all of which dampen its expression (activity). The team found that the variants increasing the risk of Alzheimer's disease are linked (inherited together) with OAS1 variants recently found to increase the baseline risk of needing intensive care for COVID-19 by as much as 20%.
Also as part of the same study, in immune cells treated to mimic the effects of COVID-19, the study team found that the gene controls how much the body's immune cells release pro-inflammatory proteins.
The team found that microglia cells where the gene was expressed more weakly had an exaggerated response to tissue damage, unleashing what they call a 'cytokine storm,' which leads to an autoimmune state where the body attacks itself.
It should also be noted that OAS1 activity changes with age, hence further research into the genetic network could help to understand why older people are more vulnerable to Alzheimer's, COVID-19, and other related diseases.
Messrs Naciye Magusali a Ph.D. student at the UK Dementia Research Institute at UCL added, "The study findings suggest that some individuals may have increased susceptibility to both Alzheimer's disease and severe COVID-19, irrespective of their age, as some of our immune cells appear to engage a common molecular mechanism in both diseases."
Upon the COVID-19 outbreak, the study team from the UK Dementia Research Institute at UCL have pivoted their attention to investigating the long-term neurological consequences of the virus.
Utilizing biomarkers found in the blood and fluid surrounding the central nervous system, the team are aiming to track neuroinflammation and injury to the neurons.
The stud team said, "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.”
The study team added, "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."
The study team concluded, “In conclusion, our study findings show that OAS1 is required to limit the pro-inflammatory response of myeloid cells when stimulated with IFN-γ. We also identify a SNP within OAS1 associated with Alzheimer’s disease in the same locus that predisposes to critical illness with COVID-19. This SNP acts as an eQTL, and is common in the population, and so may contribute to the high incidence of Alzheimer’s disease or critical illness with COVID-19 in the population. Further investigation of the function of OAS1 in innate immune cells and the genetic network engaged by OAS1 will provide better molecular targets to track disease progression and treat Alzheimer’s disease, as well as COVID-19 and potentially its long-term sequelae.”
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