Indiana University School of Medicine researchers have identified a new potential drug target for Alzheimer’s disease. The team found that removing an enzyme known as IDOL from neurons in the brain led to a significant reduction in amyloid plaques, which are commonly associated with the progression of Alzheimer’s.
Recent years have seen the approval of two drugs, lecanemab and donanemab, by the U.S. Food and Drug Administration. These drugs help remove amyloid plaques from the brain and can maintain a patient’s current level of function.
The IU research group, led by Hande Karahan, PhD, and Jungsu Kim, PhD, focused on targeting IDOL within neurons. Their findings suggest this approach could not only decrease amyloid plaque buildup but also improve communication between neurons and support lipid metabolism in the brain.
“What makes this exciting is that we now have a specific target that could lead to a new type of treatment,” said Kim, who holds the P. Michael Conneally Professorship in 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.”
In their study published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, researchers created two animal models by deleting the IDOL gene either from neurons or microglia—the immune cells of the brain.
Karahan explained that while they expected microglia to play a major role in removing amyloid plaques because these cells produce most IDOL in the brain, it was actually neuron-specific deletion that had notable effects. “Deletion of IDOL neurons not only reduced plaques,” Karahan said, “but it also reduced levels of a protein called apolipoprotein E, or APOE, that is associated with Alzheimer’s disease; one of the protein’s variants, APOE4, is the strongest risk factor for late-onset Alzheimer’s disease. APOE also plays a critical role in lipid metabolism.”
The team observed increased levels of certain receptors regulating APOE and amyloid plaques when neuronal IDOL was removed. These receptors influence both lipid metabolism and healthy neural communication. According to Karahan, recent studies indicate activating pathways controlled by these receptors may increase resilience against cognitive decline even when plaque accumulation is high.
“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.”
Kim stated that future work will involve developing strategies for targeting this enzyme as part of drug discovery efforts for Alzheimer’s treatment. He emphasized assessing compound safety and functional impact through preclinical models and determining if inhibiting IDOL preserves synaptic connections or reduces tau pathology.
Indiana University Bloomington serves as a public research university focusing on advancing research and innovation while attracting students from all 50 states and over 150 countries according to its official website. The campus features limestone architecture and has contributed significantly to Indiana’s economy and cultural landscape since its founding in 1820 [source].
The IU School of Medicine remains among the nation’s largest medical schools—offering education across nine Indiana cities—and ranked No. 13 among public medical schools for National Institutes of Health funding in 2024.
