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Studies Show ApoE4 Carriers Appear More Susceptible to COVID-19—Experts Say the Jury Is Still Out

By | February 19th, 2021

Research shows that ApoE4, the greatest genetic risk factor of Alzheimer’s, may make people more vulnerable to COVID-19. But scientists say we can’t leap to conclusions: There is still much to learn about the novel coronavirus.

Amid growing evidence of the neurological complications of COVID-19, which range from loss of sense of taste and smell, to ‘brain fog,’ to stroke and brain damage, research are trying to understand what could lead to these neurological symptoms in some patients and not others.

A recent stem cell study suggests ApoE4 may be a part of the equation, finding that the virus may worsen the effects of an infection in certain cells of the genetic variant compared to their ApoE3 counterparts. 

Vaithilingaraja Arumugaswami, an author of the study and a member of Broad Stem Cell Research Center at the University of California, Los Angeles, said the findings demonstrate that ApoE4 may be one variable that influences some people’s likelihood of experiencing severe COVID-19 symptoms.

“COVID-19 is a complex disease, and we are beginning to understand the risk factors involved in the manifestation of the severe form of the disease,” Arumugaswami said in a news release. “Our cell-based study provides a possible explanation as to why individuals with Alzheimer’s disease are at increased risk of developing more severe COVID-19 symptoms.”

In the study published in Cell Stem Cell, Arumugaswami and colleagues investigated brain cells’ response to SARS-CoV-2, the virus responsible for COVID-19, with models created from pluripotent stem cells (iPSCs), a type of stem cell that enables scientists to create virtually any type of cells and build human tissue. 

After confirming that neurons and astrocytes could indeed be infected with SARS-CoV-2, the team wondered whether the presence of astrocytes — cells that are critical to the function of the central nervous system — would aggravate a SARS-CoV-2 infection. The scientists found higher rates of infection in brain models and cell cultures with astrocytes compared to those without, an indication that astrocytes could boost the rate of a SARS-CoV-2 infection. 

The researchers then assessed whether ApoE could influence cells’ response to an infection.

Past research can offer some clues: Scientists have previously detected higher viral loads of herpes simplex virus type 1 in the brains of ApoE4 mice than ApoE3 mice. In human immunodeficiency virus, the genetic variant is linked with an accelerated progression of HIV disease compared with ApoE3. In the case of SARS-CoV-2, recent studies suggest that ApoE4 carriers are not only at higher risk of contracting the virus, but they are also more likely to develop severe complications of an infection. 

Arumugaswami and colleagues found that ApoE4 neurons and astrocytes seemed more susceptible to an infection compared to their ApoE3 counterparts.

The ApoE4 cells also responded differently to the invading virus and suffered greater damage than ApoE3 cells. Infected ApoE4 astrocytes had fatter bodies and greater fragments in the their command centers than infected ApoE3 astrocytes. Meanwhile, infected ApoE4 neurons not only had shorter signalling branches, but the cells also grew less of them. 

Current Scientific Evidence Remains Inconclusive

Dr. Aaron Ritter, associate staff of neuropsychiatry and behavioral neurology at the Cleveland Clinic Lou Ruvo Center for Brain Health who was not involved in the study, noted that there are significant differences between what happens in cells grown in petri dishes compared to the human brain.

Jessica Young, assistant professor of laboratory medicine and pathology at the University of Washington, agreed, adding that genetics is among many factors like lifestyle that influence people’s biological response to diseases. 

“Most human diseases are going to be caused by an interaction between someone’s genetics and their environment,” Young, who was not involved in the study, told Being Patient. “What’s cool about this type of work is that it separates that out. Stem cell studies can really test what the effects of genetics are. 

“[The researchers] made ApoE4 cells, compared them to ApoE3 cells, and they saw a distinct effect. That’s a very neat and powerful way to use this type of model to get at the molecular questions, as long as the caveats are understood.” 

Dr. Ritter said the study findings may not be relevant to most people as the protective barrier of the central nervous system known as the blood-brain barrier seems to be highly effective at limiting the ability of viruses to enter the brain. And, the blood-brain barrier was not included in the study, which the authors acknowledged to be a limitation of their research. 

According to Dr. Ritter, the jury is still out about whether ApoE4 carriers are at higher risk of an infection and the neurological symptoms of COVID-19. He wrote in an email, “There is still so much to be learned from this virus.”

He noted that the recent study does show that there are unknown factors including genetics that may influence biological responses to a SARS-CoV-2 infection. So, people who believe they are unlikely to develop severe complications should practice COVID-19 safety protocols just as diligently as those with well-established risk factors.  

“There are a number of factors that could make a person more susceptible to severe infection,” Dr. Ritter said, “some of these factors are well known: underlying respiratory illnesses [like chronic obstructive pulmonary disease], smoking, medical comorbidities, age, etc.  

“But this study also shows that factors we aren’t aware [of such as genetics] may play an important role at the biological level. This means that even people who may consider themselves “low risk” may, in actuality, harbor risk at a level we don’t understand. As a result, it’s still important that each one of us take all the necessary precautions to prevent transmission.” 

Contact Nicholas Chan at nicholas@beingpatient.com

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