Even a mild case of COVID-19 can cause brain changes. It's too soon to know if the damage lasts.

A new study provides the most conclusive evidence yet that COVID-19 can damage the brain, even in people who weren't severely ill.

The study, published Monday in Nature, used before-and-after brain images of 785 British people, ages 51 to 81, to look for any changes. About half the participants contracted COVID-19 between the scans – mostly when the alpha variant was circulating – which left many people at least temporarily without a sense of smell.

Analysis of the "before" and "after" images from the UK Biobank showed that people infected with COVID-19 had a greater reduction in their brain volumes overall and performed worse on cognitive tests than those who had not been infected. 

The 15 participants who were sick enough with COVID-19 to require hospitalization showed the most brain changes, but even those who had much milder disease showed differences, the study found. The oldest participants had more changes on average than younger ones.

The brain areas most affected were those that are related to smell, which makes sense, since many of the people infected around the world lost their sense of smell, said Gwenaëlle Douaud, who led the research.

People who lose their smell for prolonged periods also lose volume in brain areas related to smell. "Lose it or use it," said Douaud, a neuroscientist at Oxford University.

If smell recovers, usually the brain region does, too, she said.

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Loss of smell is one of the earliest signs of impending illness with diseases such as Parkinson's and Alzheimer's, said Dr. Ronald Petersen, who directs the Mayo Clinic Alzheimer's Disease Research Center and the Mayo Clinic Study of Aging. The olfactory structure involved in smell "lives next door" to a memory structure in the brain, he said.

The cause of the changes hasn't been determined, but they may partly be the result of the virus entering the brain or causing an inflammatory or immune response that indirectly changes the brain, Douaud said.

It's possible, she said, that the omicron variant, which seems to have less effect on sense of smell, triggered fewer brain changes than earlier variants, but it's too soon to know.

Douaud said that because brain changes appeared to increase with age in her group, she thinks younger people will probably have less damage, if any.

Dr. George Vavougios, a neuroscientist at the University of Cyprus, said it's too early to know for certain. Many people who complained of smell loss or distortions after infection were younger or previously healthy.

In his outpatient clinic, he sees no difference in brain fog complaints among people who contracted the alpha, beta or delta variants. Of those with each variant, 40% to 50% noticed cognitive impairments since their infection.

Petersen said he was struck by the fact that even people with milder cases of COVID-19 showed brain changes, and he was surprised that the changes were dramatic enough over five or six months to be detectable on brain scans.

The study spurred him to want to look at brain scans from his own research into aging to see whether he can detect similar changes. "Larger studies could shed light on this," he said.

It's unclear whether the changes will reverse. Douaud hopes to rescan the same people in a year or two to learn about long-term effects.

In a year or two, their brains "may have entirely normalized." Still, she said, "better not to catch (COVID-19), if possible, and better to be vaccinated."

It will be crucial, Vavougios said, for primary care doctors and specialists to follow their patients who had smell issues from COVID-19 and validate any complaints of brain fog.

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There are things people can do to boost their brain's resilience after a hit from COVID-19, said Patrizia Vannini, a neurologist at Brigham and Women's Hospital in Boston, who studies the infection's effect on the brain. 

"Although certain factors might make some people more resilient than other, resilience has been shown to involve behaviors, thoughts and actions which everyone can learn and develop," she said in an email.

Those include forming or maintaining social connections; adopting a healthy lifestyle, including good nutrition, sleep and exercise; seeking help when needed; and embracing "healthy thoughts by keeping things in perspective," she said. 

In a study, Vannini and her colleagues showed that older people had greater resilience during the pandemic when they used approaches such as humor to cope. Those who fared worse gave up trying to deal with the situation.

"To build up your resilience, it is important to not only enhance certain behaviors," she said, "but also reduce or avoid other behaviors."

Contact Karen Weintraub at kweintraub@usatoday.com.

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