It may be the most puzzling quirk of COVID: What manifests as minor, flu-like symptoms in some individuals turns into serious illness, disability, or even death in others. A new article published in Nature may explain the genetic underpinnings of this dichotomy.
The researchers showed that mice with genetic variants previously linked to Alzheimer’s disease had an increased risk of dying when infected with COVID. And a retrospective analysis suggested that patients with these same genetic variants were more likely to have died from COVID during the pandemic. Since three percent of the world’s population possesses these genetic variants, the findings may have implications for hundreds of millions of individuals worldwide.
“It is clear that age, sex and certain pre-existing conditions such as diabetes increase the risk of adverse outcomes, but these factors do not fully explain the spectrum of outcomes in COVID,” says Sohail Tavazoie, Leon Hess Professor at the University Rockefeller. “This is the first time we’ve seen such a common genetic variant associated with mortality from COVID.”
A closer look at APOE
In previous work, Tavazoie’s lab studied a gene called APOE that plays a role in cancer metastasis. After showing that the gene suppresses the spread of melanoma and regulates antitumor immune responses, he and his team began to study its different forms, or alleles, more closely. Most people have a form called APOE3, but 40% of the population carries at least one copy of the APOE2 or APOE4 variant. Individuals with APOE2 or APOE4 produce proteins that differ from the APOE3 protein by one or two amino acids.
An amino acid or two makes all the difference. People with APOE4 have an increased risk of developing Alzheimer’s and atherosclerosis, and Tavazoie and Benjamin Ostendorf, a postdoctoral fellow in his lab, have shown that APOE4 and APOE2 affect the immune response against melanoma. As the pandemic progressed, Tavazoie and Ostendorf began to wonder whether APOE variants might also affect COVID outcomes. “We had only looked at non-communicable diseases,” he says. “But what if APOE variants also made people vulnerable to an infectious agent, such as SARS-CoV-2? Could they cause different immune responses against a virus?”
Sohail Tavazoie (left) and Benjamin Ostendorf (right). Credit: Rockefeller University
To find out, Tavazoie and colleagues first exposed more than 300 mice engineered to carry human APOE to a mouse-adapted version of SARS-CoV-2 produced by colleagues Hans-Heinrich Hoffmann and Charles M .Rice. They found that mice with both APOE4 and APOE2 were more likely to die than those with the more common APOE3 allele. “The results were surprising,” says Ostendorf, lead author of the study. “A difference in just one or two amino acids in the APOE gene was enough to cause significant differences in the survival of mice that had COVID.”
Mice with APOE2 and APOE4 also had more virus replicating in their lungs and more signs of inflammation and tissue damage. At the cellular level, the researchers found that APOE3 appeared to reduce the amount of virus entering the cell, while animals with the other variants had less powerful immune responses to the virus. “Together, these results suggest that the APOE genotype affects the outcome of COVID in two ways,” says Ostendorf, “modulating the immune response and preventing SARS-CoV-2 from infecting cells.”
Towards clinical practice
The lab then turned to retrospective human studies. In an analysis of 13,000 patients at the UK Biobank, researchers found that individuals with two copies of APOE4 or APOE2 were more likely to have died from COVID than those with two copies of APOE3. (About three percent of people have two copies of APOE2 or APOE4, representing about 230 million people worldwide.)
Tavazoie stresses that there is no evidence that the 40 percent of individuals who carry just one of these alleles are at increased risk. He also says that those with two APOE2 or APOE4 alleles likely have a lower risk than the data indicate. “Vaccination changes the landscape,” he explains. “The UK biobank data spans the duration of the pandemic and many of the people who died early would probably have been protected if they had been vaccinated.”
Going forward, Tavazoie hopes to see prospective studies on the link between APOE and various COVID outcomes. “We’ve taken the first step,” he says. “But to be clinically useful, these results will need to be evaluated in prospective human trials that assess individuals for their APOE genotypes and take into account the availability of vaccination, something that was not available at the beginning of the pandemic and that it would improve COVID outcomes across APOE. genotypes”.
If future studies confirm a link between APOE and COVID outcomes, doctors could recommend that people with APOE4 or APOE2 be prioritized for vaccines, boosters and antiviral therapies. APOE screening is fairly routine and inexpensive, and many people already know their APOE variants because commercial genetic tests like 23andMe use it to assess Alzheimer’s risk. At the same time, Tavazoie warns that the detection of a genetic variant related to Alzheimer’s is not without ethical obstacles, given that many people would prefer not to know if they are predisposed to an incurable neurodegenerative disease.
For his part, Tavazoie plans to also look closely at how APOE interacts with various biological systems. The link between APOE4, Alzheimer’s and COVID, for example, raises the possibility that this gene may play a role in the neurocognitive complications that arise in some patients with COVID. “We want to better understand the function of APOE by studying how it shapes cell behavior in these disparate contexts of cancer, dementia and now viral infection,” he says.
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