Research News

A new Cleveland Clinic-led study has identified mechanisms by which COVID-19 can lead to Alzheimer’s disease (AD)-like dementia. The findings, published in Alzheimer's Research & Therapy, indicate an overlap between COVID-19 and brain changes common in AD, and may help inform risk management and therapeutic strategies for COVID-19-associated cognitive impairment.

Reports of neurological complications in COVID-19 patients and so-called “long-haulers” whose symptoms persist even after infection clears are becoming more common, suggesting that SARS-CoV-2 (the virus that causes COVID-19) may have lasting effects on cognitive function. However, it is not yet well understood how the virus leads to neurological issues.

“While some studies suggest that SARS-CoV-2 infects brain cells directly, others found no evidence of the virus in the brain,” says Feixiong Cheng, PhD, assistant staff in the Genomic Medicine Institute and lead author on the study. “Identifying how COVID-19 and neurological problems are linked will be critical for developing effective preventive and therapeutic strategies to address the surge in neurocognitive impairments that we expect to see in the near future.”

Here, the researchers harnessed network medicine methodologies to measure the proximity between SARS-CoV-2 host genes/proteins and those associated with several neurological diseases—including AD and dementia—where closer proximity suggests related or shared disease pathways. The researchers also analyzed the genetic factors that enabled SARS-COV-2 to infect brain tissues and cells.

While researchers found little evidence that the virus targets the brain directly, they discovered close network relationships between the virus and genes/proteins associated with several neurological diseases, most notably including AD, pointing to pathological pathways by which COVID-19 could lead to AD-like dementia. To explore this further, they investigated potential associations between COVID-19 and neuroinflammation and brain microvascular injury, which are both hallmarks of AD.

“We discovered that SARS-CoV-2 infection significantly altered AD markers implicated in neuroinflammation and that certain viral entry factors are highly expressed in brain microvascular endothelial cells,” explained Dr. Cheng. “These findings indicate that the virus may impact several genes or pathways involved in neuroinflammation and brain microvascular injury, which could lead to AD-like cognitive impairment.”

The researchers also found that individuals with APOE E4/E4, the greatest genetic risk factor for AD, had decreased expression of antiviral defense genes, which could make these patients more susceptible to COVID-19.

“Ultimately, we hope to have paved the way for research that leads to testable and measurable biomarkers that can identify patients at the highest risk for neurological complications with COVID-19,” said Dr. Cheng.  

Dr. Cheng and his team are now working to identify actionable biomarkers and novel therapeutic targets for COVID-19-associated neurological manifestations (including AD-like dementia) in COVID long-haulers using cutting-edge network medicine and and artificial intelligence technologies.

Yadi Zhou, PhD, a data scientist in Dr. Cheng’s lab; Jielin Xu, PhD; and Yuan Hou, PhD, postdoctoral fellows in Dr. Cheng’s lab, are co-first authors on the study. The study was supported by the National Institute on Aging, the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke (all parts of the National Institutes of Health) and Cleveland Clinic’s VeloSano Pilot Program.