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“Alzheimer’s-associated mutation also linked to COVID deaths”
This may be the most baffling problem with COVID: what appears as mild flu-like symptoms in some individuals that escalate to severe illness, disability or even death in others. A new paper has been published in temper nature It may explain the genetic underpinnings of this split.
The researchers showed that mice with genetic variants previously associated with Alzheimer’s disease had a higher risk of dying when infected with the COVID virus. A retrospective analysis indicated that patients with the same genetic variants were more likely to die from COVID throughout the pandemic. Since three percent of the world’s population possesses these genetic variants, the findings could have implications for hundreds of millions of individuals globally.
“It is clear that age, gender, and certain preconditions such as diabetes increase the risk of adverse outcomes, but these factors do not fully explain the scope of COVID outcomes,” he says. Sohail Tawazwe, Leon Hess Professor at Rockefeller University. “This is the first time we’ve seen such a common genetic variant associated with COVID deaths.”
A closer look at APOE
In previous work, the Tavazoie lab studied a gene called APOE that plays a role in cancer metastasis. After demonstrating that the gene prevents the spread of melanoma and regulates anti-tumor immune responses, he and his team began looking at 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.
One or two amino acids make a difference. Individuals with APOE4 are more likely to develop Alzheimer’s disease and atherosclerosis, and Tavazoy and Benjamin Ostendorf, a postdoctoral fellow in his lab, have demonstrated that APOE4 and APOE2 influence the immune response against melanoma. As the pandemic progressed, Tafazoy and Ostendorff began to question whether APOE variants might affect COVID outcomes as well. “We only looked at non-communicable diseases,” he says. “But what if APOE variants also make people susceptible to an infectious agent, such as SARS-CoV-2? Could they cause different immune responses to the virus?”
To find out, Tafazoy and colleagues exposed for the first time more than 300 mice engineered to transfer the human APOE protein into a murine adapted version of SARS-CoV-2 produced by our colleagues Hans-Heinrich Hoffmann W. Charles M. rice. They found that mice with APOE4 and APOE2 were more likely to die than mice with the most common APOE3 allele. “The results were amazing,” says Ostendorf, lead author of the study. “A difference in just one or two amino acids in the APOE gene was sufficient to make significant differences in the survival of mice presenting with COVID.”
The mice infected with APOE2 and APOE4 also had more viruses replicating in their lungs, and more signs of inflammation and tissue damage. At the cellular level, the researchers found that APOE3 appears to reduce the amount of virus entering the cell, while animals with other variants have less effective immune responses to the virus. “Together, these findings suggest that APOE genotype influences COVID outcomes in two ways, by modulating the immune response and preventing SARS-CoV-2 from infecting cells,” Ostendorf says.
towards clinical practice
Then the lab turned to human studies retrospectively. 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 die from COVID than those with two copies of APOE3. (Nearly three percent of individuals have two copies of APOE2 or APOE4, representing an estimated 230 million people worldwide.)
Tafazoy stresses that there is no evidence that 40 percent of individuals who carry only one of these alleles are at increased risk. Furthermore, he says, those with two APOE2 or APOE4 alleles are likely to be at lower risk today than the data suggest. “Vaccination changes the picture,” he explains. “The data in the UK Biobank spans the length of the epidemic, and it is likely that many individuals who died early would have been protected had they been vaccinated.”
Going forward, Tavazoie hopes to see future studies on the relationship between APOE and distinct COVID outcomes. “We have taken the first step,” he says. “But to be clinically useful, these results must be evaluated in potential human trials that test individuals for APOE genotypes and account for vaccination availability, something that was not available early in the epidemic and would improve COVID outcomes across APOE genotypes. “
If future studies confirm a link between APOE and COVID outcomes, clinicians may recommend that individuals with APOE4 or APOE2 be prioritized for vaccinations, boosters, and antiviral treatments. APOE screening is fairly routine and inexpensive, and many individuals already know their APOE variants because commercial genetic tests like 23andMe use them to measure Alzheimer’s risk. At the same time, Tafazoy warns that screening for a genetic variant associated with Alzheimer’s disease is not without ethical hurdles, given that many people prefer not to know if they are at risk of an incurable neurodegenerative disease.
For his part, Tavazoie also plans to take a closer look at how APOE interacts with different biological systems. The association between APOE4, Alzheimer’s disease and COVID, for example, raises the possibility that this gene may play a role in the neurocognitive complications that arise in some COVID patients. “We want to better understand the function of APOE by studying how it shapes cell behavior in these disparate contexts of cancer, dementia and viral infection now,” he says.
Reference: Ostendorf BN, Patel MA, Bilanovic J, et al. Common human APOE genetic variants influence the mortality rate of mice infected with COVID-19. temper nature. 2022 doi: 10.1038 / s41586-022-05344-2.
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