Common gene variant linked to COVID mortality

It may be the most baffling quirk of COVID: What manifests as minor, flu-like symptoms in some individuals spirals into severe disease, disability, and even death in others. A new paper published in Nature may explain the genetic underpinnings of this dichotomy.

The researchers demonstrated that mice with gene variants previously linked to Alzheimer's disease were at greater risk of dying when infected with COVID. And a retrospective analysis suggests that patients with those same gene variants were more likely to have died of COVID throughout the pandemic. Because three percent of the world population possesses these gene variants, the findings may have implications for hundreds of millions of individuals globally.

"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," says Sohail Tavazoie, the Leon Hess Professor at The Rockefeller University. "This is the first time that we've seen such a common genetic variant associated with COVID mortality."

A closer look at APOE

In previous work, Tavazoie's lab studied a gene called APOE that plays a role in cancer metastasis. After demonstrating that the gene suppresses 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 percent of the population carries at least one copy of the APOE2 or APOE4 variant. Individuals with APOE2 or APOE4 produce proteins that differ from APOE3 protein by one or two amino acids.

One or two amino acids make a difference. Individuals with APOE4 are at greater risk of developing Alzheimer's and atherosclerosis, and Tavazoie and Benjamin Ostendorf, a postdoctoral fellow in his lab, have demonstrated that APOE4 and APOE2 impact the immune response against melanoma. As the pandemic progressed, Tavazoie and Ostendorf began to wonder whether APOE variants might impact COVID outcomes, too. "We had looked only at non-infectious diseases," he says. "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?"

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 APOE4 and APOE2 were more likely to die than those with the more common APOE3 allele. "The results were striking," says Ostendorf, lead author on the study. "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."

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 potent immune responses to the virus. "Taken together, these results suggest that the APOE genotype impacts COVID outcomes in two ways," Ostendorf says, "by modulating the immune response and by preventing SARS-CoV-2 from infecting cells."

Toward clinical practice

The lab then turned to retrospective human studies. In an analysis of 13,000 patients in the UK Biobank, the researchers found that individuals with two copies of either APOE4 or APOE2 were more likely to have died of COVID than those with two copies of APOE3. (Roughly three percent of individuals have two copies of APOE2 or APOE4, representing an estimated 230 million people worldwide.)

Tavazoie emphasizes that there is no evidence that the 40 percent of individuals carrying only one of these alleles are at increased risk. Moreover, he says those with two APOE2 or APOE4 alleles are likely at lower risk today than the data indicates. "Vaccination changes the picture," he explains. "Data in UK Biobank spans the length of the pandemic, and many of the individuals who died early on would likely have been protected had they been vaccinated."

Moving forward, Tavazoie hopes to see prospective studies on the link between APOE and distinct COVID outcomes. "We've taken the first step," he says. "But to be clinically useful, these results will need to be assessed in prospective human trials that test individuals for their APOE genotypes and account for the availability of vaccination, something that wasn't available early in the pandemic and would improve COVID outcomes across APOE genotypes."

If future studies do confirm a link between APOE and COVID outcomes, clinicians might recommend that individuals with APOE4 or APOE2 be prioritized for vaccinations, boosters, and antiviral therapies. Screening for APOE is fairly routine and inexpensive, and many individuals already know their APOE variants because commercial genetic tests such as 23andMe use it to gauge Alzheimer's risk. At the same time, Tavazoie cautions that screening for a gene variant linked to Alzheimer's is not without ethical hurdles, given that many people would rather not know whether they are predisposed to an incurable neurodegenerative disease.

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A week in the dark rewires brain cell networks and changes hearing in adult mice

Scientists have known that depriving adult mice of vision can increase the sensitivity of individual neurons in the part of the brain devoted to hearing. New research from biologists at the University of Maryland revealed that sight deprivation also changes the way brain cells interact with one another, altering neuronal networks and shifting the mice's sensitivity to different frequencies. The research was published in the November 11, 2019 issue of the journal eNeuro.

"This study reinforces what we are learning about how manipulating vision can have a significant effect on the ability of an animal to hear long after the window for auditory learning was thought to have closed," said Patrick Kanold, professor of biology at UMD and senior author of the study.

It was once thought that the sensory regions of the brain were not adaptable after a critical period in childhood. This is why children learn languages much more readily than adults. Kanold's earlier research disproved this idea by showing that depriving adult mice of vision for a short period increased the sensitivity of individual neurons in the auditory cortex, which is devoted to hearing.

The current study expands on that earlier work. Kanold and his team investigated how exposure to darkness affects the way groups of neurons in the auditory cortex work together in response to a given sound -- which neurons are connected and which fire more powerfully or faster. The researchers placed adult mice in a dark space for one week and then played 17 different tones while measuring brain activity in the auditory cortex. Based on their earlier work, Kanold and his team expected to see changes in the neural networks, but they were surprised to find that groups of neurons changed in different ways.

Young brains wire themselves according to the sounds they hear frequently, allocating areas of the auditory cortex for specific frequencies based on what they are used to hearing. The researchers found that, in adult mice, a week in the dark also redistributed the allocation of space to different frequencies. In the areas of the auditory cortex they examined, the researchers saw an increase in the proportion of neurons that were sensitive to high and low frequencies and a decrease in proportion of neurons that were sensitive to mid-range frequencies.

"We don't know why we are seeing these patterns," Kanold said. "We speculate that it may have to do with what the mice are paying attention to while they are in the dark. Maybe they pay attention to the noises or voices from the other mice, or maybe they're paying more attention to the footsteps they are making."

Kanold said his next steps include manipulating the sounds the mice are exposed to during the darkness phase of the experiment and monitoring brain activity to determine what aspects of their soundscape the mice are listening to. This will help the researchers understand the role of focus and attention in promoting change to the auditory neurons. Such information could be very useful in helping people adapt to cochlear implants or hearing aids.

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The unpopular truth about biases toward people with disabilities

Needing to ride in a wheelchair can put the brakes on myriad opportunities -- some less obvious than one might think. New research from Michigan State University sheds light on the bias people have toward people with disabilities, known as "ableism," and how it shifts over time.

Contrary to popular belief, the findings suggest that biases toward people with disabilities increase with age and over time, but that people are less likely to show how they really feel publicly.

"Disabilities are a sensitive, uncomfortable topic for many people to talk about. Few are willing to acknowledge a bias toward people with disabilities," said William Chopik, MSU assistant professor of psychology and senior author. "Because this is so understudied, the goal of our research was to characterize why -- and which types of -- people hold higher biases against those with disabilities."

The research, published in the Journal of Social Issues, is the largest of its kind using data from 300,000 participants gathered over 13 years. Participants ranged from 18- to 90-years-old, and 15% classified themselves as having a disability.

Authors Jenna Harder, Victor Keller and Chopik used data from Project Implicit, a platform that allows users to learn and measure biases anonymously. The platform defined a disability as "some sort of physical, mental or emotional limitation" and asked a series of questions measuring feelings about people with disabilities. The researchers also measured how much contact participants had with the disability community using a scale of one to seven, one being "knowing someone" and seven being "having constant contact" with a person with a disability.

The researchers used the surveys to measure implicit attitudes and explicit bias. Harder explained that an implicit attitude are thoughts or feelings that happen automatically, which are hard to control, suppress or regulate. Explicit attitudes, she said, are the things people consciously agree with and are more controllable because it is how people express or portray their opinions about something publicly. One can think through what they are about to say and filter themselves if necessary, she said.

The researchers found that implicit bias from respondents increased over time and with age, meaning that they had less-favorable feelings toward people with disabilities. But, when asking explicitly how much participants preferred people with disabilities to be abled, they shared more positive responses with time and age, meaning that they outwardly portrayed positive opinions about people with disabilities.

"This is a big mystery because people outwardly say they feel less biased, but in actuality the implicit attitude has been getting stronger as time goes on," Chopik said. "It's not popular to express negative opinions about people with disabilities, so perhaps they feel inclined say nicer things publicly instead. Changes in explicit attitudes do not always lead to changes in implicit prejudice -- sometimes becoming more aware of a prejudice might increase implicit prejudice."

The findings also revealed that women felt less implicit bias, and that people who had contact with the disabled population had lower prejudice.

"Some of our findings related to women align with stereotypes: when you look at how men and women compare on bias, women are more compassionate toward stigmatized groups," Harder said.

"Gender was one of the most consistent predictors in this study, supporting theories that women are particularly receptive to people who they perceive as needing help."

Chopik explained that lower prejudice from people who had contact with disabled people was consistent with theories related to interactions with other stigmatized groups.

"As you interact more with a stigmatized group, you can potentially have more positive experiences with them, which changes your attitudes," he said. "You start with a certain bias, but over time those biases are challenged and your attitude changes because you have the chance to develop positive associations with the group and see them in a different light."

Data gathered from disabled participants showed feelings of warmth among their own community and a more positive attitude toward their peers. The more visible a disability -- like needing a wheelchair or a walker -- the stronger the positive attitude toward the disability community was.

Chopik emphasized the lack of research on ableism and hopes to encourage more participation from academia.

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