Researchers have long known that certain things are risk factors for severe cases of COVID-19, such as old age or obesity. But some people without any clear risk factors also experience serious, life-threatening or fatal cases. Some research has identified genetic factors that can increase a person's susceptibility to severe COVID-19. New research reported in Nature has shown that a common genetic variant, typically associated with Alzheimer's disease, is also a major risk factor for death from COVID-19.
“It is clear that age, sex, and certain preconditions such as diabetes increase the risk of detrimental outcomes, but these factors don’t fully explain the spectrum of COVID outcomes,” explained senior study author Sohail Tavazoie, the Leon Hess Professor at The Rockefeller University. “This is the first time that we’ve seen such a common genetic variant associated with COVID mortality.”
Humans carry a gene called APOE, and there are several forms or variants of this gene, which involve small changes to the APOE sequence. Some people carry APOE2, while others carry APOE3 or APOE4. It's estimated that about 40 percent of the population carries at least onecopy of either APOE2 or APOE4. These variants are not very different from one another; the APOE3 protein differs from APOE2 and APOE4 by only one or two amino acids. But those small changes lead to big impacts. APOE4 has been shown to increase a carrier's risk of developing Alzheimer’s and atherosclerosis.
Tavazoie's team has previously shown that APOE2 and APOE4 play a role in the immune response to melanoma, and wondered if APOE variants were influencing COVID-19 outcomes. They used a mouse model that carries human APOE, and exposed them to SARS-CoV-2 that was adapted to mice. Mice with APOE4 and APOE2 were found to be more likely to die from the infection compared to mice with APOE3.
“The results were striking,” said first study author Benjamin Ostendorf, a postdoctoral fellow. “A difference in just one or two amino acids in the APOE gene was sufficient to cause major differences in the survival of mice exhibiting COVID.”
There were higher levels of viral replication, more inflammation, and more tissue damage in mice with the APOE2 and APOE4 variants. Mice carrying APOE3 seemed to have less virus in their cells as well. The researchers suggested that APOE variants are influencing the cellular infection as well as the immune response to SARS-CoV-2.
The researchers then turned to human data. They found that of 13,000 patients in the UK Biobank, people with two copies of APOE4 or APOE2 were more likely to die from COVID-19. About three percent of people, or around 230 million people around the world are thought to carry two copies of either APOE2 or APOE4.
The researchers noted that a single copy of one of those variants does not seem to influence the risk of severe COVID-19, however. There is also preventive medicine.
“Vaccination changes the picture,” Tavazoie added. “Data in UK Biobank spans the length of the pandemic, and many of the individuals who died early on would likely have been protected had they been vaccinated.”
The researchers are interested in whether human trials might be conducted to see how people with APOE variants are impacted, and what their vaccination status is. If a link is conclusively demonstrated, it may be possible to screen infected individuals to see who might be at risk of a more severe infection. However, people would then also know whether they have a predisposition to Alzheimer's disease, which may be information they don't want to know.
Tavazoie also wants to know more about how APOE interacts with various biological processes. “We want to better understand the function of APOE by studying how it shapes the behavior of cells in these disparate contexts of cancer, dementia and now viral infection,” he said.
Sources: Rockefeller University, Nature