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

An antiviral gene that affects the risk of both Alzheimer’s disease and severe Covid-19 has been identified by a UCL-led research team.

The researchers estimate that one genetic variant of the OAS1 gene increases the risk of Alzheimer’s disease in the population as a whole by about 3-6%, while related variants on the same gene increase the likelihood of severe Covid-19 outcomes.

The findings, published in Brain, could open the door to new targets for drug development or tracking disease progression in both diseases, and suggest that developed treatments could be used for both conditions. The findings also have potential benefits for other related infectious conditions and dementias.

Lead author Dr. Dervis Salih (UCL Queen Square Institute of Neurology and UK Dementia Research Institute at UCL) said: “Although Alzheimer’s disease is mainly characterized by damaging amyloid protein buildup and tangles in the brain, there is also extensive inflammation in the brain highlighting the importance of the immune system in Alzheimer’s disease We found that some of the same changes in the immune system can occur in both Alzheimer’s and Covid-19.

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

For the study, the research 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.

The OAS1 gene is expressed in microglia, a type of immune cell that makes up about 10% of all cells in the brain. To further investigate the gene’s link to Alzheimer’s disease, they sequenced the genetic data of 2,547 people, half of whom had Alzheimer’s disease. They found that people with a particular variation, called rs1131454, of the OAS1 gene were more likely to have Alzheimer’s disease, increasing the baseline risk of the Alzheimer’s carrier by an estimated 11-22%. The new variant identified is common, as slightly more than half of Europeans are believed to be the carrier, and has a greater impact on Alzheimer’s risk than several known risk genes.

Their findings add OAS1, an antiviral gene, to a list of dozens of genes now known to influence a person’s risk of developing Alzheimer’s disease.

The researchers examined four variants of the OAS1 gene, all of which dampen its expression (activity). They found that the variants that increase the risk of Alzheimer’s disease are linked (inherited together) with OAS1 variants that have recently been found to increase the baseline risk of intensive care for Covid-19 by as much as 20%.

As part of the same study, in immune cells treated to mimic the effects of Covid-19, the researchers found that the gene controls how much the body’s immune cells release pro-inflammatory proteins. They found that microglia cells where the gene was more weakly expressed had an exaggerated response to tissue damage, leading to what they call a “cytokine storm,” leading to an autoimmune state where the body attacks itself.

OAS1 activity changes with age, so further research into the genetic network could help understand why older people are more vulnerable to Alzheimer’s disease, Covid-19 and other related diseases.

PhD candidate Naciye Magusali (UK Dementia Research Institute at UCL) said: “Our findings suggest that some people have an increased susceptibility to both Alzheimer’s disease and severe Covid-19, regardless of age, as some of our immune cells share a common molecular mechanism. in both diseases.”

Following the outbreak of the Covid-19 pandemic, researchers at UCL’s UK Dementia Research Institute have turned their attention to examining the long-term neurological consequences of the virus. Using biomarkers found in the blood and fluid around the central nervous system, they try to detect neuroinflammation and injury to the neurons.

dr. Salih said: “If we could develop a simple way to test these genetic variants when someone tests positive for Covid-19, it might be possible to identify who is at greater risk of needing critical care, but there’s a lot more work to do to get us there. Likewise, we hope our research can help develop a blood test to determine whether a person is at risk for developing Alzheimer’s before exhibiting memory problems.

“We also continue to investigate what happens once this immune network is activated in response to an infection such as Covid-19, to see if it leads to lasting effects or vulnerabilities, or if we understand the brain’s immune response to Covid-19, where involving the OAS1 gene may help explain some of the neurological effects of Covid-19.”

Reference: “A genetic link between Alzheimer’s disease risk and severe COVID-19 outcomes via the OAS1 gene” by Naciye Magusali, Andrew C Graham, Thomas M Piers, Pantila Panichnantakul, Umran Yaman, Maryam Shoai, Regina H Reynolds , Juan A Botia , Keeley J Brookes, Tamar Guetta-Baranes, Eftychia Bellou, Sevinc Bayram, Dimitra Sokolova, Mina Ryten, Carlo Sala Frigerio, Valentina Escott-Price, Kevin Morgan, Jennifer M Pocock, John Hardy and Dervis A Salih, 7 October 2021, Brain .
DOI: 10.1093/brain/awab337

The study involved researchers from UCL, University of Nottingham, Cardiff University and Nottingham Trent University. The work was funded by the UK Dementia Research Institute (DRI), which receives its funding from the DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. Further support was provided by Alzheimer Nederland, Erasmus, the Horizon 2020 program of the European Union, the European Federation of Pharmaceutical Industries and Associations and the National Institute for Health Research UCLH Biomedical Research Centre.