Scientists Uncover New Alzheimer’s Drug Target That Slashes Brain Plaques

A newly identified enzyme target may open an alternative path for treating Alzheimer’s disease.

Scientists at the Indiana University School of Medicine have identified a potential new drug target for Alzheimer’s disease. Their research shows that removing a specific enzyme from brain neurons significantly lowers amyloid plaque buildup, a defining feature of the disease, and may also help the brain better resist further damage.

In recent years, the U.S. Food and Drug Administration has approved two treatments for Alzheimer’s disease. These drugs, lecanemab and donanemab, clear amyloid plaques from the brain and can “freeze” a person in their current level of function.

Targeting the IDOL Enzyme

The research team, led by Hande Karahan, PhD, and Jungsu Kim, PhD, focused on an enzyme called IDOL. They found that reducing IDOL activity in neurons may offer a new way to lower amyloid levels while also improving how brain cells communicate and manage lipids.

“What makes this exciting is that we now have a specific target that could lead to a new type of treatment,” said Kim, the P. Michael Conneally Professor of Medical and Molecular Genetics. “We believe that IDOL will provide us with an alternative strategy to treat Alzheimer’s disease. Targeting enzymes in drug development offers key advantages due to their well-defined active sites or ‘pockets’ where drugs can attach and block their activity. This precision means we can design molecules that hit the right target with minimal side effects.”

The study, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, used two animal models of Alzheimer’s disease. In these models, researchers removed the IDOL gene either from neurons or from microglia, which are immune cells in the brain.

Karahan, an assistant research professor of medical and molecular genetics, said the team initially expected microglia to play the main role in clearing amyloid plaques. This assumption was based on the fact that immune cells are central to amyloid removal and are the primary source of IDOL in the brain.

Unexpected Effects in Neurons

However, removing IDOL from neurons produced strong effects. It reduced amyloid plaques and also lowered levels of apolipoprotein E, or APOE, a protein closely linked to Alzheimer’s disease. One variant, APOE4, is the strongest genetic risk factor for late onset Alzheimer’s disease. APOE is also essential for lipid metabolism.

The researchers also observed an increase in receptors that regulate both APOE and amyloid plaques when IDOL was removed from neurons. These receptors play an important role in lipid metabolism and in maintaining healthy communication between neurons. Karahan noted that other research has shown activating a related pathway may help protect against cognitive decline in patients with high plaque levels.

“This is especially important from a clinical perspective because patients are usually diagnosed with the disease after accumulating substantial amyloid plaque load in the brain. Not only decreasing amyloid levels but also increasing resilience to these pathological changes could maximize clinical benefits,” Karahan said. “Targeting neuronal IDOL may offer multiple therapeutic benefits in Alzheimer’s disease by simultaneously reducing amyloid burden while enhancing neuroprotective effects.”

Next Steps in Drug Development

Kim said the team plans to explore several approaches to target IDOL as part of new Alzheimer’s treatments. This includes testing the safety and effectiveness of potential compounds in preclinical models. The researchers will also study whether blocking IDOL can help preserve synaptic connections and reduce tau pathology, another key feature of the disease.

Reference: “Deletion of neuronal Idol ameliorates Alzheimer’s disease–related pathologies via APOE receptors” by Hande Karahan, Kelly Hartigan, Md Mamun Al-Amin, Sutha K. John, Brianne McCord, H. R. Sagara Wijeratne, Dominic J. Acri, Daniel C. Smith, Luke C. Dabin, Hannah M. Rondon Cordero, Byungwook Kim, Do-Hun Lee and Jungsu Kim, 12 December 2025, Alzheimer’s & Dementia.
DOI: 10.1002/alz.70949

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