Scientists Reveal Biological Signal Behind Mysterious Alzheimer’s Drug Side Effect

A hidden immune signature may quietly determine who develops side effects from Alzheimer’s therapy.

Scientists at the University of Kentucky have uncovered a biological signal that may help explain one of the most concerning side effects tied to new Alzheimer’s treatments. Their findings suggest that a simple blood test could one day identify which patients are more likely to develop complications before therapy even begins.

The study, published in Nature Communications, focuses on amyloid-related imaging abnormalities (ARIA), a condition that can cause brain swelling or small areas of bleeding visible on MRI scans. ARIA has emerged as a key safety concern for anti-amyloid drugs such as lecanemab, the first therapy shown to slow Alzheimer’s disease progression. While these drugs represent a major step forward, uncertainty around ARIA risk has limited how widely they can be used.

Until now, predicting who will develop ARIA has largely relied on genetics. People who carry the APOE ε4 gene variant are known to face higher risk, but that explanation has been incomplete. Many patients without the variant still develop complications, while others with it do not. This gap has made treatment decisions difficult for clinicians and families alike.

“We asked a simple question: do people who develop ARIA show a different immune ‘fingerprint’ in their blood than those who don’t? The answer appears to be yes,” said Josh Morganti, Ph.D., assistant professor of neuroscience and researcher at the University of Kentucky’s Sanders-Brown Center on Aging.

To investigate, the team analyzed blood samples from patients treated with lecanemab at Norton Neuroscience Institute in Louisville. Using detailed genetic and metabolic profiling, they found that patients who developed ARIA had increased levels of a specific subset of T cells. These immune cells showed heightened metabolic activity and appeared primed to respond.

“This isn’t random noise. We’re seeing a coordinated immune response that distinguishes patients with ARIA at a biological level,” he said.

A Blood Test Instead of Invasive Procedures

One of the most important findings is that this immune signal can be detected through a standard blood test rather than invasive procedures.

“Until now, we really didn’t understand why some people develop ARIA and others don’t,” Morganti explained. “And we can’t biopsy someone’s brain to figure that out. This study shows that we can learn something meaningful from the blood, which is an important step if we ever want to turn these findings into a real-world screening tool.”

Lance Johnson, Ph.D., associate professor of physiology and researcher at Sanders-Brown, said the findings set the stage for a more personalized approach to Alzheimer’s care. “We now know that ARIA isn’t just an imaging artifact. There’s biology behind it that we can measure. That means we have something to work with,” said Johnson.

Previously, the main known risk factor for ARIA was genetic. People who carry the APOE ε4 gene variant face a higher risk, but the biological processes behind that risk were unclear. This study offers new insight by showing that certain T cells expand, change their metabolism, and gain the ability to interact with blood vessels.

“This suggests ARIA may have a biological signature we can detect in the blood,” Johnson said.

A path toward prediction and better treatment

The researchers hope their findings will lead to safer and more accessible Alzheimer’s therapies. With further validation in larger groups of patients, these immune patterns could form the basis of a predictive blood test to identify those at higher risk before treatment begins.

“If we can validate these findings in larger groups, clinicians could adjust treatment, closer monitoring, different dosing schedules or even targeted interventions, based on a patient’s immune profile,” Morganti said. “For people and families facing an Alzheimer’s diagnosis, anything that makes these new treatments safer and more accessible is meaningful.”

Johnson added, “Right now, ARIA is a cloud hanging over these otherwise groundbreaking therapies. If we can use this work to help predict or even prevent these side effects, it will be a big step forward.”

Both researchers emphasized that more work is needed, but the study moves the field beyond speculation toward measurable biological markers.

Collaboration, support, and gratitude

The University of Kentucky team also highlighted the essential role of their collaborators at Norton Neuroscience Institute and Norton Research Institute in Louisville.

“I’m incredibly proud of the work our team has done to bring hope to patients facing an Alzheimer’s diagnosis,” said Gregory E. Cooper, M.D., Ph.D., chief of adult neurology and director of the Norton Neuroscience Institute Memory Center. “These findings have the potential to significantly improve the safety and precision of care for patients undergoing anti-amyloid therapy. This collaboration is a powerful example of what can be achieved when experts unite around a shared purpose. I look forward to building on this momentum as we continue advancing research and improving the lives of those affected by Alzheimer’s disease.”

Johnson and Morganti said the partnership demonstrates how academic research can be strengthened through collaboration with community-based clinical programs.

“Lecanemab-treated patients represent a rare and difficult-to-access population. Dr. Cooper and his team’s energy and enthusiasm to collaborate, coordinating care and research sample collection during active treatment, made this work possible,” Morganti said.

Reference: “Clonal expansion of cytotoxic CD8⁺ T cells in lecanemab-associated ARIA” by Lance A. Johnson, Kai Saito, Akhil V. Pallerla, Jessica L. Funnell, Ashley R. Ezzo, Chelsea M. Song, Douglas A. Harrison, Noah J. Norton, Lauren C. Moore, Linda J. Van Eldik, David W. Fardo, Greg E. Cooper and Josh M. Morganti, 30 January 2026, Nature Communications.
DOI: 10.1038/s41467-026-68921-3

Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers R01AG081421 and R01AG080589, the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number RF1NS118558, the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number TL1TR001997 and the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P20GM148326.

Research reported in this publication was also supported by the Alzheimer’s Association under grant ABA-25-1376140.

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