A new study suggests that people with two copies of ApoE4, one of the largest genetic risk factors for Alzheimer’s, have more than double the risk of getting a severe COVID-19 infection. But other researchers heed caution against drawing conclusions too soon.
In the study, a team of researchers at the University of Exeter Medical School and the University of Connecticut drew data from the UK Biobank which has data on 500,000 volunteers aged 48 and 86. They looked for positive COVID-19 tests between March and April, and then compared the presence of ApoE4 alleles with the severity of COVID-19.
Why Does ApoE Matter and What’s Its Relationship with COVID-19?
Everyone has two copies of the ApoE gene, but there are several variations, including ApoE2, ApoE3 and ApoE4. The combination you have determines your ApoE genotype — E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, or E4/E4.
ApoE3 is the most common and doesn’t seem to influence risk for Alzheimer’s, while the E4 allele, which is present in 10 to 15 percent of people, increases the risk for Alzheimer’s and lowers the age of onset. Having one copy of E4 can double or triple your risk, and having two copies — E4/E4 — can increase Alzheimer’s risk by a factor of 12.
The team found that those with two copies of ApoE4 had over double the risk of severe COVID-19 than those with ApoE3.
“This is an exciting result because we might now be able to pinpoint how this faulty gene causes vulnerability to COVID-19. This could lead to new ideas for treatments,” said Chia-Ling Kuo in a press release, an author of the study and senior biostatistician at University of Connecticut.
What Are The Limitations of the Study?
“It’s impressive that the researchers were able to analyze this data so quickly,” Aaron Ritter, associate staff of neuropsychiatry and behavioral neurology at Cleveland Clinic Lou Ruvo Center for Brain Health, told Being Patient in an email statement.
But Ritter cautioned that there may be other factors affecting the results: “We know very little about the populations being analyzed,” he said.
Indeed, the researchers did not have data about whether the study participants had mild cognitive impairment, and lived in nursing homes. According to David Melzer, an author of the study and professor of epidemiology and public health at University of Exeter, the latest available data about study participants’ dementia diagnoses was 2017.
Ritter added, “My biggest concern is that given the [mean] age of those being analyzed — 68 years old — the relationship between COVID-19 and the gene ApoE4 could be more affected by the patient’s cognitive status than genetic status.”
He noted that people who carry two copies of ApoE4 are likely to have some form of cognitive impairment by the age of 68. They may forget to take their medications, be in poorer overall health, and forget to keep their hands clean, all of which could be variables in their increased likeliness for contracting COVID-19.
“My biggest concern is that given the [mean] age of those
being analyzed, the relationship between COVID-19 and the
gene ApoE4 could be more affected by the patient’s
cognitive status than genetic status.”
Axel Montagne, Associate Professor of Research Physiology & Neuroscience at University of Southern California, said it is too early to conclude that ApoE4 increases people’s risk of contracting COVID-19: “[The study] is very interesting but you have to take it with a grain of salt.”
Montagne pointed out that some participants may have developed dementia after 2017. Also, some may have lived in nursing homes where there are high rates of infections.
“This study, which I would consider preliminary data, is important and a step in the right direction,” Ritter said. “If verified in a larger study with younger, better characterized patient participants, it would help us understand why some people may be at higher risk for serious complications from COVID-19.”
While the link between COVID-19 and ApoE4 is still up for debate, it is clear that the virus impacts the brain. Past research shows that about 36 percent of patients with COVID-19 develop symptoms such as headache, numbness or tingling and impaired consciousness. Autopsy reports reveal that patients suffer from swelling and inflammation in the brain, and the degeneration of neurons.
Just as it is too soon to take the recent study’s suggestions as conclusive evidence, it is too soon to discount them. Past research suggests that indeed, ApoE4 can meddle with the body’s immune responses.
“ApoE proteins are involved in immune response to infections,” said Stephen Dominy, co-founder and Chief Scientific Officer of biopharmaceutical company Cortexyme. “It’s possible that ApoE4, for example, is not as good at the immune response to SARS-CoV-2 infections of COVID-19.”