Enlarged choroid plexus in Long COVID linked to Alzheimer’s disease biomarkers

A neuroimaging study from NYU Langone Health has reported that people with neurological Long COVID show enlargement and reduced blood flow in the choroid plexus – a key brain structure – with changes that track blood markers associated with Alzheimer’s disease and measurable cognitive decline

Researchers at NYU Langone Health, New York, USA, have reported that structural and vascular changes in a critical brain region among patients with Long COVID are similar to established blood biomarkers of Alzheimer’s disease and also with poorer performance on cognitive tests. The findings strengthen concerns that persistent immune activation after infection with COVID-19 may contribute to long-term neurological risk.

The study focused on the choroid plexus, a specialised network of blood vessels and epithelial cells within the brain ventricles that produces cerebrospinal fluid. This fluid cushions the brain, supports waste clearance and forms a tightly regulated barrier between the bloodstream and the central nervous system. The choroid plexus also plays a central role in immune signalling within the brain. Previous research has shown that infection with the coronavirus which is responsible for COVID-19 disease can damage the cells that line its blood vessels.

The study found that individuals who reported persistent neurological symptoms after COVID-19 infection had choroid plexuses that were – on average – about 10 per cent larger than those observed in people who had fully recovered from infection. Enlargement of this structure was not seen to the same extent in participants who had never been infected.

Importantly, increases in choroid plexus size compared favourably with blood concentrations of proteins that rise as Alzheimer’s disease progresses, including phosphorylated tau at threonine 217. Enlargement also correlated with higher levels of markers associated with brain injury, such as glial fibrillary acidic protein.

These molecular changes were accompanied by subtle but measurable differences in cognition. Participants with larger choroid plexuses scored an average of about two per cent lower on the ‘Mini-Mental State Examination’, a widely used 30-point screening tool that assesses memory, attention and other cognitive domains.

“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 Dr. Yulin Ge, professor of radiology at the NYU Grossman School of Medicine and senior author of the study.

“Physical, molecular and clinical evidence suggests that a larger choroid plexus may be an early warning sign of future Alzheimer’s-like cognitive decline,” he said.

Long COVID refers to a constellation of symptoms that persist for months or years after the acute phase of infection has been resolved. These symptoms can include fatigue, cognitive impairment often described as brain fog, dizziness, loss of smell or taste, mood disturbance and a wide range of other neurological and systemic effects. Around 800 million people worldwide have been infected with the virus to date and a substantial minority have reported prolonged symptoms.

To investigate potential brain correlates of these long-term effects, the research team recruited 179 participants. This cohort included 86 individuals with neurological symptoms consistent with Long COVID, 67 people who had recovered from COVID-19 without lasting effects and 26 participants with no history of infection. All participants underwent advanced magnetic resonance imaging of the brain alongside blood testing and cognitive assessment.

Analysis of the imaging data showed that – in Long COVID patients – structural alterations within the choroid plexus were accompanied by reduced blood flow through its vessels. Although the precise biological mechanisms remain to be confirmed, the investigators proposed that chronic inflammation may drive a process of vascular remodelling. In this model, prolonged immune activation leads the cellular layers lining blood vessels to thicken, while surrounding stromal fibrosis develops as scar-like tissue accumulates. Together, these changes would restrict blood perfusion.

Reduced blood flow through the choroid plexus has several plausible downstream consequences. Impaired perfusion may limit the production of cerebrospinal fluid, promote the accumulation of metabolic waste within the brain and weaken the integrity of the blood–cerebrospinal-fluid barrier. Each of these effects could plausibly contribute to cognitive dysfunction and to longer-term neurodegenerative processes.

“Our next step is to follow these patients over time to see if the brain changes, we identified can predict who will develop long-term cognitive issues,” said Dr. Thomas Wisniewski, who is the ‘Gerald J. and Dorothy R. Friedman Professor of Neurology’ at the NYU Grossman School of Medicine and a senior author of the study.

“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,” he added.

While the findings do not establish that Long COVID causes Alzheimer’s disease, they provide converging anatomical, molecular and cognitive evidence that persistent post-infectious inflammation may place stress on brain systems that have already been implicated in dementia. As longitudinal data is gathered, the choroid plexus may prove to be an important early indicator of neurological vulnerability in the aftermath of COVID-19 infection.

For further reading please visit: 10.1002/alz.71020