What are the links between COVID-19, brain harm and dementia risk?

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Headaches, brain fog and that peculiar inability to smell or taste things. By now most people know these symptoms as a few of the hallmarks of COVID-19. Researchers say they are a clear indication the virus impacts neurological functions.

But what that impact means to long-term brain health remains unclear. With preliminary research hinting at a relationship between COVID-19 and Alzheimer's susceptibility, investigators are eager to learn whether the neurological damage caused by COVID-19 will be short-lived, or if it could lead to greater cognitive decline in an aging population.

Thus far, said Dr. Eliezer Masliah, director of the division of neuroscience at the National Institute on Aging, "we don't know a lot."

Investigators hope to gain insight through a massive multidisciplinary research project announced earlier this year by the National Institutes of Health, which committed $470 million to study the long-term health consequences of COVID-19, including how it affects brain health. The Researching COVID to Enhance Recovery (RECOVER) initiative will fund large-scale studies of a wide range of populations through grants to more than 100 investigators at 30 institutions nationwide.

To assist with this research, NIH is building a national database of neurological symptoms, complications and outcomes experienced by people infected with COVID-19 – as well as biological specimens collected from doctors' offices and research sites.

Investigators are looking at the relationship between COVID-19 and the brain from two perspectives, Masliah said. "One is what happens during an acute infection and the other is what are the long-term consequences after the infection."

Since the pandemic began, research shows more than 90% of people infected with the virus have reported at least one neurological symptom, with many reporting more. What's troubled health experts is these symptoms often linger long after the infection clears.

Cognitive impairment covers a range of issues, including memory, language and attention. It can affect how people interact with others and their environment.

Jaqueline Becker, a New York City neuropsychologist, led research published in JAMA Network Open in October that found cognitive problems among people with a wide range of COVID illness severity. One of the most common was a decline in executive function skills, which allow people to plan, focus, follow instructions and multitask.

The risk for cognitive impairment rose as people got sicker, said Becker, an associate scientist at the Icahn School of Medicine at Mount Sinai in New York City.

"We found those who were hospitalized were more likely to have cognitive impairments in the area of attention, executive function, memory coding and memory recall than those who were treated as outpatients," she said.

Poor executive function also can impact memory and the speed at which the brain can process information, Becker said.

Because executive function impairment is associated with the development of dementia, "there is concern about later neurodegeneration in the post-COVID population," she said. However, whether it will persist over time – or whether one could recover those skills – remains to be seen. Becker's study of middle-aged adults includes data up to one year post-COVID, but she and the researchers at Mount Sinai will continue collecting this data for at least another four years.

"There are implications for neurodegenerative disorders," she said. "We hope that, at least in healthy, young patients, this will resolve over time. But we still don't know."

Some scientists believe one way to reduce the potentially higher risk for dementia may be through COVID-19 vaccinations – and not simply because they protect against infection and serious illness.

Prior studies suggest inoculations such as the flu vaccine may offer some protection against dementia because they help strengthen the immune system. Masliah said researchers involved in RECOVER will be looking at whether COVID vaccines likewise reduce dementia risk.

"It would not be an outlandish hypothesis to think that would be protective as well, but we don't have data yet," he said.

In the meantime, Becker said people experiencing post-COVID neurological symptoms should not jump to conclusions about the long-term consequences. They should, however, visit a primary care physician if problems persist to rule out other causes.

For example, she said, "depression can affect cognition function, and oftentimes, as depression lifts, so does the cognitive impairment."

Another mystery is why the virus is harming the brain. It could happen in multiple ways.

There's some controversial evidence to suggest the virus might be infecting the brain. Other studies suggest changes in blood vessels may be responsible for cognitive disruption.

"Either the blood vessels are retracting, or being obstructed, or there are other types of vascular changes," Masliah said. He pointed to studies that found damage to the brain's white matter caused by vascular changes from COVID infection.

Others are looking into whether inflammation in the brain is responsible for the neurological symptoms, he said.

One study published early this year in the journal Cells suggests inflammation persists after COVID recovery and may alter important proteins associated with dementia. The findings in participants recovering from infections showed increased amyloid beta and tau – two proteins responsible for the development of Alzheimer's disease generated by neuroinflammation.

Another avenue of investigation looks at the genetic risk for Alzheimer's disease and how it aligns with greater susceptibility to severe COVID-19. Research published in October in the journal Brain showed a gene associated with inflammation and a higher susceptibility for Alzheimer's was being expressed in response to COVID-19 infection.

"This is something quite dramatic," Masliah said. "But it is still very preliminary. What is the relationship between Alzheimer's and COVID-19 at the moment is not really known. There is a tremendous amount of work going on there."

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