Recent brain imaging shows the disease can cause physical changes equivalent to a decade of aging and trigger problems with attention and memory. Exactly why is still a mystery.
By Sanjay Mishra
After being bedridden with fever and coughing for three and half days, Elena Katzap thought COVID-19 was behind her. The writer and teacher in Los Angeles had contracted the virus at the end of January 2022, and she felt grateful that she got only a mild case—she didn’t have breathing difficulties and didn’t need to be hospitalized, and she recovered within days.
“I very specifically remember saying, God it feels so good to be healthy again,” says Katzap. “Then all of a sudden, the very next day it smacked me, and I didn’t know what it was, because it started off with nausea and some stomach issues and some weird forgetfulness.”
Katzap has since experienced an acute loss of memory with poor concentration. She draws blanks in the middle of conversations, and words fail her mid-sentence. “It isn’t physically painful, but it’s so frustrating,” she laments.
Of the roughly 80 million Americans who’ve gotten COVID-19 so far, about one of every four survivors suffers from impaired cognition, commonly described as brain fog. While this isn’t a formal medical term, says Edward Shorter, a professor of psychiatry at University of Toronto, it has become an umbrella term for describing an array of symptoms such as confusion, word-finding difficulties, short-term memory loss, dizziness, or inability to concentrate.
Patients hospitalized with COVID-19 are almost three times more likely than those not hospitalized to have impaired cognition. But brain scans now show that even a mild case of COVID-19 can shrink part of the brain, causing physical changes equivalent to a decade of aging.
“There is evidence of neurologic injury [after COVID-19] that is persistent,” says Ayush Batra, a neurologist at Northwestern University Feinberg School of Medicine. “We are seeing biological and biochemical evidence of it, we are seeing radiographic evidence of it, and most importantly, the patients are complaining of their symptoms. It is affecting their quality of life and day-to-day functioning.” Batra together with his colleagues, has shown chemical indicators of injured brain neurons among long COVID patients with neurologic symptoms.
The drastic impact of COVID-19 on brain
Some of the most compelling evidence of neurological damage after mild COVID-19 comes from U.K. researchers who investigated brain changes in people before and after they got the disease.
The 785 participants, between 51 and 81 years old, who had already been scanned before the start of the pandemic, were scanned on average three years apart as part of the U.K. Biobank project. Tests or medical records showed that 401 of these volunteers had become infected with SARS-CoV-2. Most had mild infections; only 15 of the 401 were hospitalized.
In the region of the brain linked to smell, the COVID-19 patients had 0.7 percent more tissue damage compared to healthy people.
The infected participants’ performance on cognitive tests also declined more rapidly than before illness. They took 8 and 12 percent longer on the two tests that measured attention, visual screening ability, and processing speed. The patients were not significantly slower on memory recall, reaction time, or reasoning tests.
“We could in turn relate this greater mental ability decline to their greater loss of gray matter in a specific part of the brain,” says Gwenaëlle Douaud, a neuroscientist at the University of Oxford who led the U.K. study.
Overall, studies consistently show that COVID-19 patients score significantly lower in tests of attention, memory, and executive function compared to healthy people. Jacques Hugon, a neurologist at University of Paris Lariboisiere Hospital, says it isn’t clear if the brain will mend itself or whether patients will ever recover, even with cognitive rehabilitation.
“We don’t know exactly what’s going on in the brain,” says Hugon. Perhaps the damage COVID-19 causes in the brain will evolve into various neurodegenerative disorders. “We don’t know that for sure at the moment, but it is a risk, and we need to follow [the patients] very carefully for the years to come.”
What causes brain fog and cognitive decline?
Even before COVID-19, viral infections were known to cause long-lasting cognitive impairments; it is well established that viral infections significantly increase the world’s burden of neurological diseases. While there’s no consensus yet on the exact cause of COVID-19’s cognitive impacts, its effects on various organs can be catastrophic, which means there are many ways the disease can be affecting the brain.
Because COVID-19 affects respiration, it can starve the brain of oxygen, as seen in autopsy data from Finland. In rare cases, COVID-19 can also damage the brain by causing encephalitis, a form of brain inflammation. More broadly, COVID-19 can elicit a severe immune response that triggers a storm of proteins called cytokines, which amplify inflammation throughout the body. Long-term inflammation has been shown to promote cognitive decline and neurodegenerative disease and so could be causing neurodegeneration among COVID-19 survivors.
COVID-19 also increases the risk for blood clots for up to six months, which can cause strokes that deprive the brain tissue of oxygen. One study found large stray bone marrow cells—responsible for the production of blood-clotting platelets—lodged in the brain capillaries of individuals who died from COVID-19 infection. These cells could cause strokes in COVID-19 patients and trigger some neurologic impairments.
Some scientists even fear that COVID-19 survivors could be at higher risk for Alzheimer’s disease, based on evidence for a protein called beta-amyloid in the brains of younger patients who died of COVID-19.
Studies are also accumulating that show direct evidence of the SARS-CoV-2 virus invading the brain. A study by the U.S. National Institutes of Health, currently under review, illustrates how SARS-CoV-2 can spread well beyond the lungs and the respiratory tract. This study suggests that the inability of the immune system to clear the virus from the body could be a potential contributor to long COVID symptoms, including brain fog.
Counting mild COVID-19 cases
Beyond pinpointing the causes, one major concern is that it’s difficult to get an accurate count of how many COVID-19 patients have developed cognitive issues, in part because these symptoms don’t always manifest immediately after infection.
This was the case for Richard Newman, a U.S. Army veteran who is now an IT manager in Houston, Texas. He suffered a severe COVID-19 infection in June 2021 and spent two weeks in the ICU. But he didn’t experience cognitive problems, including trouble recognizing people, until a month after he was discharged from the hospital.
“I knew the face, I knew I was supposed to know them, but I couldn’t remember their name,” says Newman. His symptoms have not improved much eight months after he was first diagnosed with COVID-19. “It is very horrible, it is very debilitating, and it really affects your quality of life,” he says.
At least one study shows that two-thirds of COVID-19 survivors seen at 59 hospitals in the U.S. were diagnosed with cognitive issues during a six-month follow-up. However, as the recent U.K.-based study shows, even mild cases can put people at risk, and tracking those patients will be a challenge if they don’t make the connection between mild COVID-19 and any neurological symptoms that pop up later. Other survivors may be reluctant to mention their experience with COVID-19 and subsequent neurological problems for fear of stigma and discrimination.
Experts also worry that between the wide availability of vaccines and the rise of the relatively milder Omicron variants, people are letting their guard down too soon because they’re not concerned about the possible cognitive damage from getting sick. Although COVID-19 vaccines are highly effective in protecting against serious illness, they do not protect against “long COVID” in people who become infected despite vaccination.
“We need to move away from quantifying the impact of the disease only in terms of deaths and severe cases,” says the University of Oxford’s Douaud, “as evidence from studies on long COVID, and our study, show that even mild infection can be damaging.”