Scientists found a hidden Alzheimer’s trigger and shut it down

The discovery comes as scientists continue searching for improved treatments for Alzheimer’s. In recent years, the U.S. Food and Drug Administration approved two disease modifying drugs, lecanemab and donanemab, which work by clearing amyloid plaque buildup in the brain. These treatments can help stabilize patients by slowing further decline.

The Indiana University team believes targeting IDOL could offer a different strategy for fighting Alzheimer’s while also improving communication between brain cells and supporting healthy lipid metabolism.

“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.”

Brain Cell Experiments Reveal Surprising Results

The findings were published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. Researchers created two separate animal models of Alzheimer’s disease by deleting the IDOL gene in different brain cell types, including neurons and microglia, which are immune cells in the brain.

Scientists originally expected microglia to play the larger role in clearing amyloid plaques because these immune cells help remove harmful material from the brain and are the primary producers of IDOL.

Instead, the most striking effects appeared when IDOL was removed from neurons.

Hande Karahan, PhD, assistant research professor of medical and molecular genetics, said deleting IDOL in neurons not only lowered plaque levels but also reduced levels of apolipoprotein E (APOE), a protein strongly associated with Alzheimer’s disease. One form of the protein, APOE4, is considered the greatest genetic risk factor for late onset Alzheimer’s disease. APOE is also important for regulating lipid metabolism in the brain.

Potential Benefits Beyond Plaque Removal

Researchers also found increased levels of receptors involved in regulating APOE and amyloid plaques after the enzyme was removed from neurons. These receptors are important for maintaining healthy communication between neurons and supporting lipid metabolism.

Karahan said earlier research has shown that activating a related pathway may help people with Alzheimer’s remain more resistant to cognitive decline, even when significant plaque accumulation is present.

“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.”

Researchers Plan Future Alzheimer’s Drug Development

The research team is now exploring several approaches for developing drugs that target the IDOL enzyme. According to Kim, future studies will focus on testing the safety of potential compounds and evaluating how well they work in preclinical models.

Scientists also plan to investigate whether blocking IDOL can preserve synaptic connections between neurons and reduce tau pathology, another major feature of Alzheimer’s disease.