We only know these are more common in COVID-19 patients.
As the pandemic reshaped the boundaries of medical knowledge, researchers at the University of Georgia turned to one of the largest human health datasets ever assembled to ask which hidden vulnerabilities the virus was exploiting. What emerged was both a scientific finding and a moral reckoning: cognitive disorders and dementia, conditions already carrying heavy burdens, quietly placed their bearers among those most at risk of severe COVID-19. The discovery arrived not from a predetermined hypothesis but from the data itself — a reminder that the most consequential truths are sometimes the ones we were not yet looking for.
- Cognitive disorders and dementia — conditions absent from early pandemic warning lists — surfaced as the strongest disease-based risk factors for severe COVID-19 in one of the largest analyses of its kind.
- The study's scale amplified its urgency: nearly 1,000 diseases were examined across a dataset of more than 500,000 participants, making the silence around cognitive vulnerability in early public health guidance all the more striking.
- A specific genetic variation in the TMPRSS2 gene appeared disproportionately in COVID-19 patients, suggesting that inherited biology may quietly determine who faces the gravest outcomes.
- Researchers were candid about the boundary of their findings — the associations were clear, but the mechanisms driving them remained unknown, leaving a critical scientific gap even as the virus continued to spread.
- The study's most urgent implication was institutional: populations with cognitive disorders had not been explicitly prioritized for protection, and the data suggested they should have been from the very beginning.
In the early months of the pandemic, researchers at the University of Georgia set out to identify which pre-existing conditions made people most vulnerable to severe COVID-19. Their findings, published in Brain, Behavior and Immunity, pointed somewhere unexpected: cognitive disorders and dementia emerged as statistically significant risk factors — conditions that had been largely overlooked in early public health guidance.
The team, led by assistant professor Kaixiong Ye and postdoctoral researcher Jingqi Zhou, drew on the UK Biobank — a long-running study tracking the medical histories and genetic data of more than 500,000 participants. When the biobank began recording COVID-19 test results in March 2020, it created a rare opportunity to compare the health profiles of those who contracted the virus against those who did not.
Taking what Ye called a hypothesis-free approach, the researchers examined nearly 1,000 diseases for patterns distinguishing COVID-19 patients from negative controls. Two conditions rose immediately to the top: cognitive disorders first, Type 2 diabetes second. "Right now, we do not know the mechanisms behind these associations," Ye acknowledged. "We only know these are more common in COVID-19 patients."
The team also investigated the genetic underpinnings of COVID-19 severity, focusing on the ACE2 and TMPRSS2 genes — both critical to how the virus enters human cells. A specific variation in TMPRSS2 appeared more frequently among COVID-19 patients, suggesting that inherited differences may shape who develops severe, hospitalization-requiring illness.
The implications were sobering. People with cognitive disorders and dementia, already among society's most vulnerable, had not been explicitly prioritized for protective measures in the early pandemic response — and the data suggested they should have been. The researchers had mapped the associations and some of the genetic terrain, but the underlying mechanism remained hidden, awaiting further investigation even as the virus continued its spread.
In the early months of the pandemic, researchers at the University of Georgia began asking a straightforward question: which pre-existing conditions made a person more vulnerable to severe COVID-19? What they found, published in the journal Brain, Behavior and Immunity, pointed to an unexpected answer. Cognitive disorders and dementia emerged as statistically significant risk factors—conditions that had not been prominently flagged in early pandemic guidance, yet appeared to correlate strongly with worse outcomes.
The study drew on an enormous dataset. Researchers accessed information from the UK Biobank, a long-running health study that had enrolled more than 500,000 participants and tracked their medical histories alongside genetic information. Beginning in March 2020, as the pandemic took hold, the biobank began recording which of its participants had tested positive for COVID-19. This created a rare opportunity: a team led by assistant professor Kaixiong Ye and postdoctoral researcher Jingqi Zhou, both in the genetics department at the Franklin College of Arts and Sciences, could now compare the health profiles of people who had contracted the virus against those who had not.
The scope of the analysis was ambitious. The researchers examined data on nearly 1,000 different diseases, looking for patterns that distinguished COVID-19 patients from the negative controls. They took what Ye described as a hypothesis-free approach—they were not testing a predetermined theory, but rather letting the data reveal which conditions appeared most frequently in the COVID-19 group. Two findings stood out immediately. Cognitive disorders topped the list. Type 2 diabetes came second. "Right now, we do not know the mechanisms behind these associations," Ye said in explaining the results. "We only know these are more common in COVID-19 patients."
The team also examined the genetic architecture underlying COVID-19 severity. They focused on two genes known to play a critical role in how the virus enters human cells: ACE2 and TMPRSS2. In the TMPRSS2 gene, they identified a specific genetic variation that appeared more frequently in COVID-19 patients. This suggested that inherited differences in how people's cells respond to the virus might influence who develops severe disease and who does not. The researchers found that variations in genes related to SARS-CoV-2 infection could be associated with more severe illness—the kind that requires hospitalization.
The implications were sobering. People with cognitive disorders and dementia, already vulnerable in many ways, now appeared to face elevated risk of not just contracting COVID-19, but of becoming severely ill. The finding underscored a gap in pandemic preparedness: these populations had not been explicitly prioritized for protective measures or special care protocols in the early response. The research suggested they should have been. Yet the study also revealed the limits of what science could explain at that moment. The researchers had identified the associations, mapped some of the genetic terrain, but could not yet explain why cognitive disorders correlated with severe COVID-19. The mechanism remained hidden. Understanding it would require further investigation—work that would take time even as the virus continued to spread.
Notable Quotes
We took a hypothesis-free approach and the most statistically significant ones are the cognitive disorders and Type 2 diabetes.— Kaixiong Ye, assistant professor at University of Georgia
The Hearth Conversation Another angle on the story
Why would cognitive disorders specifically make someone more vulnerable to severe COVID-19? That's not an obvious connection.
That's exactly what the researchers couldn't answer. They found the association was real and statistically significant, but the mechanism—the actual biological reason—remained unclear. It could be genetic, it could be related to how people with cognitive disorders manage their health, it could be something about their immune response. They just didn't know yet.
So they identified a risk factor without understanding why it's a risk factor?
Yes. And that's actually valuable information in a crisis. You don't always have time to understand the why before you need to act. If you know a population is at higher risk, you can prioritize them for protection even while research continues.
Did the genetic findings help explain anything?
Partially. They found variations in genes that control how the virus enters cells. Some people's cells may be more or less susceptible based on their genetics. But that doesn't directly explain why someone with dementia would be hit harder.
What about Type 2 diabetes? That's a metabolic condition, not neurological.
Right. It also appeared in their data as a significant risk factor. So they had two very different types of conditions flagged—one neurological, one metabolic. That suggests the vulnerability might come from multiple different pathways, not a single mechanism.
What happens next with this research?
Other teams would need to investigate the mechanisms. Why does cognitive impairment correlate with severe COVID? Is it about immune function, about ability to manage illness, about something in the biology itself? That's the work that follows.