Shared genetic risk factor identified between Covid-19 and Alzheimer’s disease

A team of researchers from UK DRI at UCL have identified an anti-viral gene that impacts the risk of both Alzheimer’s disease and severe Covid-19. The findings, published today (7 Oct) in Brain, could open the door for new targets for drug development or tracking disease progression in either disease, with the possibility of shared treatments.

For the new study led by Dr Dervis Salih from UK DRI at UCL, the 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 constitutes around 10% of all cells found within the brain. The researchers estimate 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 were recently found to increase the baseline risk of needing intensive care for Covid-19 by as much as 20%.

Lead author Dr Dervis Salih, UK DRI at UCL and UCL Queen Square Institute of Neurology. 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.”

Investigating the gene’s link to Alzheimer’s, the authors sequenced genetic data from 2,547 people, half of whom had Alzheimer’s disease. While investigating four variants of the OAS1 gene, they found that people with rs1131454 were more likely to have Alzheimer’s disease, increasing carriers’ baseline risk of Alzheimer’s by an estimated 11-22%. 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. Their 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. 

As part of the same research, 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 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. OAS1 activity changes with age, so 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.

Following the outbreak of the Covid-19 pandemic, researchers from the UK DRI at UCL have pivoted their attention to investigating the long-term neurological consequences of the virus. Using biomarkers found in the blood and fluid surrounding the central nervous system, they are aiming to track neuroinflammation and injury to the neurons.

Dr Salih 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.

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 involved researchers at UCL, University of Nottingham, Cardiff University, and Nottingham Trent University. The work was funded by the UK Dementia Research Institute (UK DRI), which receives its funding from the UK 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 European Union’s Horizon 2020 programme, the European Federation of Pharmaceutical Industries and Associations and the National Institute for Health Research UCLH Biomedical Research Centre.

Reference

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, Dervis A Salih, A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene, Brain, 2021;, awab337, https://doi.org/10.1093/brain/awab337

Article published: 08 October 2021
Banner image: CI Photos/Shutterstock.com
Microglia image courtesy of NIH