Alzheimer’s and COVID-19 share a genetic risk factor

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

Researchers believe that a genetic variant of OAS1 gene increases the risk of Alzheimer’s disease by about 3-6% in the general population, while related variants on the same gene increase the likelihood of severe COVID-19 outcomes.

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

Lead author Dr Dervis Salih (UCL Queen Square Institute of Neurology and UK Dementia Research Institute at UCL) said: “While Alzheimer’s disease is primarily characterized by a harmful build-up of amyloid proteins and tangles in the brain, there is also brain inflammation which highlights the importance of the immune system in Alzheimer’s disease.We have found that some of the same changes in the immune system can occur in both Alzheimer’s disease and in COVID-19.

“In patients with severe COVID-19 infection, there may also be inflammatory changes in the brain. Here, we have identified a gene that may contribute to an exaggerated immune response to increase the risk of Alzheimer’s and of 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. By further studying the gene’s link to Alzheimer’s disease, they sequenced the genetic data of 2,547 people, half of whom suffered from 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 carriers of Alzheimer’s disease by about 11 to 22%. The new variant identified is common, because just over half of Europeans are believed to be carriers, and it has a greater impact on the risk of Alzheimer’s than several known risk genes.

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

The researchers studied four variants of the OAS1 gene, all of which attenuate its expression (activity). They found that the variants that increase the risk of Alzheimer’s disease are related (inherited together) with OAS1 Newly discovered variants increase the baseline risk of needing intensive care for COVID-19 by up to 20%.

In the same research, in immune cells treated to mimic the effects of COVID-19, the researchers found that the gene controls the amount of pro-inflammatory proteins released by the body’s immune cells. They found that the cells in the microglia where the gene was expressed more weakly had an exaggerated response to tissue damage, triggering what they called a “cytokine storm,” which leads to an autoimmune state where the body goes. 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 student Naciye Magusali (UK Dementia Research Institute at UCL) said: “Our results suggest that some people may have an increased susceptibility to both Alzheimer’s disease and severe COVID-19, regardless of their age, because some of our immune cells seem to engage a molecular mechanism in both diseases.

After the outbreak of the COVID-19 pandemic, researchers at UCL’s UK Dementia Research Institute focused their attention on studying the long-term neurological consequences of the virus. Using biomarkers found in the blood and fluid surrounding the central nervous system, they aim to track neuroinflammation and damage to neurons.

Dr Salih said: “If we could develop a simple way to test for these genetic variants when a person is positive for COVID-19, then it would be possible to identify who is most at risk of needing intensive care. , but there is much more.Likewise, we hope that our research can fuel the development of a blood test to identify if a person is at risk for developing Alzheimer’s disease before they have memory problems.

“We also continue to research what happens after this immune network has been activated in response to an infection like COVID-19, to see if it causes lasting effects or vulnerabilities, or if understanding the immune response brain to COVID-19, involving the OAS1 gene, may help explain some of the neurological effects of COVID-19. ”