Could Long COVID Brain Changes Signal Future Cognitive Decline?

Pandemics leave a lasting impact on the brain. More than one million survivors of the 1918 flu pandemic developed a virally-triggered form of Parkinson’s. COVID infections are also showing signs of impacting the brain in various ways 

Initial COVID-19 infection has been linked with overall brain shrinkage, altered brain structure, and an increased risk of being diagnosed with Alzheimer’s. Long COVID — the persistent aftermath of the infection that has affected as many as one in ten — is also leading to lingering neurological problems, such as memory lapses and cognitive problems.

A recent study published in the journal Alzheimer’s & Dementia found changes in brain structure and blood flow in long COVID that might explain the cognitive symptoms, focusing on a walnut-sized brain structure called the choroid plexus which produces the cerebrospinal fluid that bathes the brain and helps clear out waste. 

“Our work suggests that long-term immune reactions caused in some cases after an initial COVID infection may come with swelling that damages a critical brain barrier in the choroid plexus,” said senior study author Dr. Yulin Ge, a professor in the department of radiology at NYU Grossman School of Medicine, in a press release. 

These brain changes might signal future “Alzheimer’s-like cognitive decline,” though more research is needed to know for sure, the study said. 

Does long COVID set the stage for Alzheimer’s?

Ge and his team recruited 179 participants — 86 with long COVID who had neurological symptoms, 67 who recovered from COVID-19 without developing long COVID, and 26 healthy controls who were never infected. The groups were uneven. The long COVID group was on average 10 years older, with far higher rates of drinking, hypertension, and high cholesterol. 

All participants received MRI scans, blood tests to look for biomarkers of inflammation and Alzheimer’s proteins, and cognitive tests. Those with long COVID or a previous COVID-19 infection had a slightly larger choroid plexus than the healthy controls. The choroid plexus was largest in the long COVID group, suggestive of inflammation. Since this region of the brain is increased, it may mean nearby regions of brain cells, gray matter, have shrunk.

Susan Landau, a research neuroscientist at the University of California, Berkeley, who wasn’t involved in the study, told Being Patient that “the groups were not matched for age or clinical status or other health symptoms,” which could also explain the choroid plexus and grey matter.

The study found that people with long COVID also had reduced blood flow. But this could also be driven by other factors like alcohol use, high blood pressure, and cholesterol, making it difficult to say whether the changes are solely caused by long COVID.

Neurological impairments caused by long COVID aren’t always captured by existing cognitive tests. In the study, there were no significant differences between the long COVID group, the recovered COVID group, or healthy controls across four such tests. However, a higher proportion of those with long COVID had mild cognitive impairment (MCI) compared to the other groups.

The larger choroid plexus was linked to higher levels of an inflammatory blood biomarker called GFAP and an Alzheimer’s biomarker pTau-217 in those with long COVID. However, the study did not report on whether these biomarkers correlated with these changes in any of the other groups, which “makes it impossible to determine that the associations they report are unique to long COVID,” said Landau.

Alzheimer’s blood biomarkers are not well-validated outside the context of people with cognitive symptoms suspected to have Alzheimer’s so it is unclear what they mean within the context of Long COVID. 

Last year, a study found that a COVID-19 infection increased the levels of some Alzheimer’s biomarkers, but some experts were skeptical because they claimed the test the researchers used wasn’t accurate. 

Another study recently published by some of the same researchers followed 260 older adults over the course of more than 4 years. Those that developed long COVID were more likely to develop any form of mild cognitive impairment as well as the Alzheimer’s-linked subtype of the disease.  

What’s next for neurological long COVID research?

Neuropsychologists studying long COVID are working on new ways to measure and detect signs of cognitive impairment. 

The researchers plan to follow participants over time to see whether any of the changes in the brain predict cognitive decline or Alzheimer’s later on, and to guide new treatments. So far, attempts to treat neurological symptoms in long COVID haven’t panned out. The NIH-funded RECOVER-NEURO trial tested brain games, cognitive training, electrical stimulation — none worked.

“A larger, long-term study will be needed to clarify whether these choroid plexus alterations are a cause or a consequence of the neurological symptoms, which promises to better focus treatment design efforts,” senior study author Dr. Thomas M. Wisniewski, professor of the New York University Alzheimer’s Disease Research Center and  director of the Center for Cognitive Neurology at NYU Langone said in a press release.