Common flu drugs show promise in preventing cognitive decline

A recent study suggests that a loss of protective sugar molecules in the body contributes to the cognitive decline and premature aging often seen in people living with chronic viral infections like HIV. The findings provide evidence that common flu medications might be repurposed to preserve these sugar molecules, offering a potential new way to protect brain health. The research was published in the journal Med.

The research team was led by scientists at Northwestern University, including Mohamed Abdel-Mohsen, a Margaret Gray Morton associate professor of medicine in the division of infectious diseases at Northwestern University Feinberg School of Medicine. Abdel-Mohsen is also a member of the Center for Human Immunobiology, the Potocsnak Longevity Institute, and the Third Coast Center for AIDS Research.

The researchers set out to understand why at least a quarter of people living with HIV develop problems with memory and thinking. These cognitive issues can occur even when modern antiretroviral medications successfully keep the virus under control in the bloodstream.

“People living with HIV are now living much longer because of effective antiretroviral therapy, which is a major success,” Abdel-Mohsen told PsyPost. “However, many still experience chronic inflammation, accelerated aging-related changes, and problems with memory or thinking.” Over time, chronic viral infections can cause a continuous, low-level immune response in the body. This constant immune activity leads to a biological phenomenon known as inflammaging, which is a combination of chronic inflammation and accelerated biological aging.

This state of constant high alert can eventually damage healthy tissues, including the brain, leading to cognitive issues. The scientists focused their attention on glycans, which are complex sugar molecules attached to proteins in the blood and on the surface of cells. These sugars normally act as a calming signal for the immune system, helping to prevent excessive inflammation.

“Our lab studies glycans, the sugar molecules that decorate cells and proteins, because they are powerful regulators of immunity and inflammation but are still often overlooked,” Abdel-Mohsen said. “We wanted to understand whether changes in these protective glycans could help explain why chronic viral infection continues to affect the immune system and brain even when HIV is well controlled.”

The team wanted to see if the loss of these specific sugars was connected to cognitive decline in people with HIV. They also wanted to test if blocking the enzymes that destroy these sugars could prevent inflammation and protect memory. The enzymes that remove these sugars are called sialidases. Interestingly, common flu drugs are actually sialidase inhibitors, meaning they are designed to block this exact type of enzyme to stop the flu virus from spreading.

To explore this connection, the scientists first analyzed blood samples from a long-term health tracking project. They examined a group of forty individuals with HIV who were taking effective antiviral medications. Twenty of these participants were men and twenty were women. Half of the group had been formally diagnosed with cognitive impairment, while the other half had normal cognitive function based on standard clinical tests.

The researchers tracked these individuals over an eight-year period, collecting between five and nine blood samples per person. They used a specialized laboratory technique to measure the specific types of sugar molecules attached to immune proteins in the blood. The results showed that participants with cognitive impairment had a greater continuous loss of protective sugars compared to those with normal memory function. This loss correlated directly with poorer scores on cognitive tests.

“In our study, we found that degradation of protective glycans, that normally protect our bodies from excessive inflammation but we normally lose them as we get older, were degraded at a faster pace in people with HIV and cognitive impairments (especially women) than what would be normal for their age,” Abdel-Mohsen explained.

Next, the scientists validated these findings in a separate cross-sectional group of eighty people with HIV. This validation group also included forty men and forty women, evenly split between those with and without cognitive impairment. The researchers found the same pattern of sugar degradation in the impaired group.

They also measured standard inflammatory markers in the blood, but found that the sugar degradation was a much more accurate indicator of cognitive issues than basic inflammation. Interestingly, the loss of these protective sugars was significantly more pronounced in women than in men. Women with cognitive impairment exhibited a much higher loss of sialic acid and galactose than women without cognitive issues.

The scientists suggest this difference might be related to hormonal shifts over a person’s lifespan. Sugar degradation tends to accelerate in women around the time of menopause, potentially creating a period of increased vulnerability for the brain. “I was also struck by the stronger glycan signal in women, which suggests that sex, hormonal biology, and menopause may be important factors in this pathway,” Abdel-Mohsen said.

Following the human data, the team conducted laboratory experiments using human immune cells to see if they could stop the damage. They exposed the immune cells to sialidases, the enzymes that naturally strip away sialic acid. As expected, this exposure triggered a strong inflammatory response, causing the cells to release harmful chemicals. The researchers then treated the cells with sialidase inhibitors, the class of drugs that includes the common flu medication oseltamivir, known commercially as Tamiflu.

They combined oseltamivir with an experimental drug called DANA. This combination successfully prevented the loss of the protective sugars. As a result, the cells stopped releasing inflammatory signals, remaining in a calm, healthy state. To test this approach in a living system, the scientists used a specialized model of mice that were biologically modified to have human immune cells.

They infected these humanized mice with HIV and gave half of them a daily oral dose of the flu drug combination. The researchers tracked the immune health and viral levels in the mice for five weeks, comparing them to untreated infected mice and healthy uninfected mice. The untreated mice developed high levels of systemic inflammation and showed signs of accelerated epigenetic aging. Epigenetic aging refers to chemical modifications on DNA that change how genes are expressed, serving as a biological clock for the body.

The mice treated with the flu drugs experienced significantly less inflammation and immune system exhaustion. The daily treatment also prevented the accelerated epigenetic aging seen in the untreated animals. Because that specific humanized mouse model cannot be used for complex behavioral tests, the authors utilized a second animal model. They infected standard laboratory mice with a modified version of HIV designed specifically to infect mouse cells.

Twenty-five days after the initial infection, the researchers began treating a portion of the mice with the flu drug combination using a daily nasal spray for ten days. The scientists then tested the animals’ spatial learning and memory using a radial arm water maze. This test requires the mice to swim and find a hidden platform in a pool of water over several days of training trials. The untreated infected mice made significantly more errors and struggled to remember the location of the platform from day to day.

In contrast, the mice treated with the flu drugs performed just as well as healthy, uninfected mice. The treatment completely prevented the virus-induced memory deficits. The researchers also examined the brain tissue of these animals after the behavioral tests were completed to understand what was happening at a cellular level. They found that the drug treatment preserved the protective sialic acid sugars directly in the brain.

The treated brains showed reduced markers of neuroinflammation and normalized gene expression. In addition, the treatment prevented the buildup of proteins commonly associated with neurodegeneration, such as amyloid and tau proteins, which are often implicated in dementia.

“One surprising aspect was how well the different parts of the study came together,” Abdel-Mohsen said. “We started with glycan patterns in blood samples from people with HIV, then tested the mechanism in cells and animal models, and found that protecting these glycans could reduce inflammation and cognitive problems in mice.”

“Importantly, we found that preserving these glycans from being degraded, using a class of drugs usually used to treat the flu, in animal models reduced inflammation, aging-related changes, and memory problems,” Abdel-Mohsen added. “This points to a new mechanism and a possible future therapeutic direction.”

“The main message is that sugar molecules in the body are not just passive decorations; they can actively regulate inflammation, aging-related biology, and possibly brain health.”

While these findings provide evidence for a new therapeutic approach, there are some limitations to consider. The sample sizes in the human observation studies were relatively small. All the participants with HIV were already taking effective antiviral medications, so it is unclear how these sugar changes behave in untreated individuals. Larger observational studies that track individuals before and after cognitive issues develop will be necessary to confirm if these sugar changes can reliably predict future memory decline.

“The human part of the study shows an association between glycan degradation and cognitive impairment, but it does not prove by itself that glycan degradation causes cognitive decline in people,” Abdel-Mohsen said. “The treatment effects were shown in preclinical models, not in human clinical trials.”

“Also, although some sialidase inhibitors are already used clinically for influenza, they have not been tested for this purpose, dose, duration, or long-term safety,” he continued. “People should not take flu drugs for memory problems based on this study.” He reiterated, “But it is very important to emphasize that this is not a recommendation for people to take flu medications to prevent or treat memory problems.” Future research will focus on developing better medications that specifically target the enzymes responsible for sugar degradation in humans.

Scientists also plan to investigate exactly how sex hormones, like estrogen, might influence the production and loss of these protective sugar molecules. Expanding this research could eventually lead to new treatments that protect the brain during long-term viral infections and other aging-related diseases.

“Our next goals are to better understand how these protective glycans are lost during chronic HIV infection and aging, to optimize strategies to preserve them, and to determine whether glycan-based blood biomarkers can predict who is at risk for future cognitive decline or other aging-related complications,” Abdel-Mohsen said. “We also want to develop safer and more targeted approaches, which may or may not be the same drugs currently used for influenza.”

“Ultimately, the goal is to move from understanding this mechanism to designing clinical studies that test safety, target engagement, and eventually whether this approach can improve healthspan in people living with HIV and possibly in broader aging-related diseases,” he noted. “I think this study highlights a broader point: as people with HIV live longer, the next major challenge is not only preserving lifespan, but also preserving healthspan.”

“We need to understand why chronic inflammation and aging-related complications persist despite excellent antiviral therapy. Glycans may give us a new window into that biology and may eventually help us develop new diagnostics and therapies.”

The study, “Inhibiting glycan degradation prevents HIV-induced inflammaging and cognitive impairment,” was authored by Leila B. Giron, Alejandra Borjabad, Eran Hadas, Janeway Granche, Erika G. Marques de Menezes, Thomas A. Premeaux, Hongxia He, Stephen T. Yeung, Shalini Singh, Courtney Friday, Joshua Glover, Eric Balboa, Derrick Dopkin, Michelle Burrows, Anthony Secreto, Nicolas Skuli, Hiroaki Tateno, Paul W. Denton, Frank Palella, Michael J. Corley, Lishomwa C. Ndhlovu, Philip J. Norris, Katherine Tassiopoulos, David J. Volsky, and Mohamed Abdel-Mohsen.