New Alzheimer’s disease treatment targets an enzyme

Scientists at the Indiana University School of Medicine say they have uncovered a promising new strategy for treating Alzheimer’s disease by targeting an enzyme in the brain that appears to play a central role in plaque buildup and neuronal health.

In a study published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, the research team found that removing an enzyme known as IDOL from neurons substantially reduced amyloid plaques — one of the hallmark features of Alzheimer’s disease. The findings suggest that blocking the enzyme could lead to a new class of treatments aimed at slowing or potentially altering the course of the disease.

Over the past several years, the U.S. Food and Drug Administration has approved two disease-modifying drugs for Alzheimer’s — lecanemab and donanemab — both designed to remove amyloid plaque buildup in the brain. These medications can help stabilize patients, effectively “freezing” them in their current functional state. However, researchers continue to search for additional therapeutic strategies that may provide broader or longer-lasting benefits.

Treatment targets an enzyme

The IU team, led by Hande Karahan, Ph.D., assistant research professor of medical and molecular genetics, and Jungsu Kim, Ph.D., the P. Michael Conneally Professor of Medical and Molecular Genetics, focused on IDOL, an enzyme involved in regulating lipid metabolism and neuronal communication.

“What makes this exciting is that we now have a specific target that could lead to a new type of treatment,” Kim said. “We believe that IDOL will provide us with an alternative strategy to treat Alzheimer’s disease.”

Enzymes are often attractive drug targets because they have clearly defined active sites — or “pockets” — where medications can bind and block activity. That precision, Kim explained, makes it possible to design drugs that hit the intended target while minimizing side effects.

To investigate IDOL’s role, researchers generated two separate animal models of Alzheimer’s disease. In one model, they deleted the IDOL gene in neurons. In the other, they removed it from microglia, the brain’s immune cells.

Surprising results

The researchers initially expected microglia to be the main driver of plaque clearance, since immune cells play a key role in removing amyloid and are the primary source of IDOL in the brain. Instead, they found that deleting IDOL from neurons produced the most striking results.

Removing IDOL from neurons not only reduced amyloid plaques but also lowered levels of apolipoprotein E (APOE), a protein strongly associated with Alzheimer’s risk. One variant of the protein, APOE4, is considered the strongest genetic risk factor for late-onset Alzheimer’s disease. APOE also plays an essential role in lipid metabolism within the brain.

In addition, the team observed increased levels of certain receptors that regulate both APOE and amyloid plaques when IDOL was removed from neurons. These receptors are important for lipid metabolism and healthy communication between neurons. 

According to Dr. Karahan, emerging research suggests that activating pathways controlled by these receptors may help protect against cognitive decline, even in individuals 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,” Karahan said. “Not only decreasing amyloid levels but also increasing resilience to these pathological changes could maximize clinical benefits.”