COVID-19 has been perplexing, to put it lightly. For the past three years, we’ve seen a variety of different symptoms, severities, and outcomes on an individual basis. We know that things like age, sex, and certain underlying medical conditions have an influence on how COVID affects a person. But new research published in Nature shows there might be another explanation for why some people have more severe COVID cases than others.
The APOE Gene Could Be To Blame
The ability to determine who is at risk for deadly and incapacitating COVID cases has been a major sticking point for scientists. But recent research from The Rockefeller University indicates that the APOE gene could be a major player when it comes to COVID infections.
In their study, researchers found that mice with gene variants previously linked to Alzheimer’s disease were at greater risk of dying when infected with COVID. In their retrospective analysis, it was suggested that human COVID patients with those same genetic mutations—which are found in 3% of the world’s population, or approximately 240 million people—were more likely to have died during the pandemic.
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“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,” Sohail Tavazoie, the Leon Hess Professor at The Rockefeller University, told Futurity. “This is the first time that we’ve seen such a common genetic variant associated with COVID mortality.”
The Difference Between APOE Variants
Tavazoie’s lab had previously studied the APOE gene, which plays a role in cancer metastasis. It’s known to regulate tumor-fighting immune responses and suppress the spread of melanoma.
Most people have a form of the APOE gene called APOE3, but 40% of us actually carry at least one copy of the APOE2 or APOE4 variant. Individuals with these variants (also called alleles) produce proteins that differ by just one or two amino acids compared to APOE3—and according to Tavazoie’s research, that difference has a massive impact.
Those with the APOE4 variation are at greater risk for Alzheimer’s, which is what prompted Tavazoie and his team to wonder if APOE variants could possibly affect COVID outcomes, too.
“We had looked only at non-infectious diseases,” he said. “But what if APOE variants also made people vulnerable to an infectious agent, like SARS-CoV-2? Could they cause different immune responses against a virus?”
APOE And COVID-19 Severity
After exposing more than 300 mice engineered to carry human APOE to COVID, Tavazoie and his team found that those with APOE4 and APOE2 were more likely to die than those with the more common APOE3 form. They also had more virus replicating in their lungs, more signs of inflammation, and more signs of tissue damage.
“The results were striking,” lead study author Benjamin Ostendorf shared with Futurity. “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.”
When they took their study results and analyzed 13,000 human COVID patients in the UK Biobank, the researchers found that individuals with two copies of APOE4 or APOE2 were more likely to have died from the virus.
What The Research Suggests
In his research, Tavazoie makes it clear there is no evidence that the 40% of people carrying only one of the alleles are at increased risk. He also says that the 3% of the population with two APOE2 or APOE4 alleles are probably at lower risk today than the research indicated because of the vaccine.
He explained that the data in the UK Biobank is from the entire pandemic, and it’s possible that those who died early on may have been protected against dire outcomes if they’d been vaccinated. However, he would like to see more research done on the link between APOE and specific COVID outcomes.
“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,” Tavazoie said.
This research may help us learn more about how COVID works, but human trials that account for vaccination are necessary in order for the results to be clinically useful. If future research does confirm the link between APOE and COVID outcomes, that could help when it comes to prioritizing individuals for vaccinations, boosters, and antiviral therapies.