Indianapolis, Indiana – Scientists at Indiana University School of Medicine say they have uncovered a promising new pathway that could reshape how Alzheimer’s disease is treated, offering fresh hope in a field that has long struggled to slow the condition’s relentless progression. Their findings center on a specific enzyme in the brain that appears to play a critical role in the buildup of amyloid plaques — one of the most recognizable biological features of the disease.
Alzheimer’s disease, a degenerative brain disorder that gradually erodes memory, thinking skills, and independence, affects millions of people worldwide. In recent years, treatments approved by the U.S. Food and Drug Administration have begun to target amyloid plaques directly. Two such medications, lecanemab and donanemab, are designed to remove these protein deposits, helping stabilize patients by slowing functional decline rather than reversing damage.
But researchers in Indianapolis believe their discovery could open a different and potentially powerful avenue. The team, led by Hande Karahan and Jungsu Kim, identified an enzyme known as IDOL as a key factor influencing plaque formation and brain cell health. Their experiments showed that when the enzyme was removed specifically from neurons — the cells responsible for transmitting signals throughout the brain — amyloid plaque levels dropped significantly.
The implications, researchers say, go beyond plaque reduction alone. The enzyme also appears closely tied to lipid metabolism and communication between neurons, two processes essential for maintaining healthy brain function. By influencing both, targeting IDOL could potentially address multiple aspects of Alzheimer’s disease at once.
“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.”
To explore the enzyme’s role, the scientists created two separate animal models of Alzheimer’s disease. In one, they removed the IDOL gene from neurons; in the other, they removed it from microglia, the brain’s immune cells that normally help clear harmful substances. Initially, the team expected the microglia-based approach to have the greatest impact, since immune cells play a central role in removing amyloid deposits.
Instead, the opposite happened. Eliminating IDOL within neurons proved far more effective at reducing plaque levels.
Karahan explained that the neuronal deletion produced additional benefits. It lowered levels of apolipoprotein E, commonly known as APOE, a protein strongly linked to Alzheimer’s risk. One variant, APOE4, is considered the most significant genetic risk factor for late-onset Alzheimer’s disease. APOE also plays a major role in lipid metabolism, influencing how fats are processed and transported in the brain.
The researchers also observed increases in certain receptors involved in regulating both APOE and amyloid plaques. These receptors are known to help maintain healthy communication between neurons and support lipid balance — factors that can protect against cognitive decline.
A recent study cited by the team found that activating a pathway controlled by these receptors can strengthen resilience in patients who already have high levels of amyloid buildup. That connection suggests that targeting IDOL may not only reduce harmful plaques but also help the brain withstand damage more effectively.
“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.”
For scientists, the discovery represents a step forward in understanding the complex web of processes that drive Alzheimer’s progression. While amyloid plaques have long been a central focus of research, many experts now believe effective treatments must also address other biological pathways — including inflammation, metabolism, and communication between neurons.
Kim said the next phase of research will focus on translating these findings into potential therapies. His team plans to explore several strategies for inhibiting the IDOL enzyme, while carefully evaluating safety and effectiveness in preclinical models. One key question will be whether blocking IDOL can preserve synaptic connections, the critical junctions that allow neurons to communicate.
Researchers also intend to investigate whether IDOL inhibition could reduce tau pathology — another hallmark of Alzheimer’s disease involving tangles of abnormal proteins inside brain cells.
The work highlights the broader research strength of Indiana University’s medical school, the largest in the United States and a major center for neurological research. The institution consistently ranks among the nation’s top recipients of federal biomedical funding and operates campuses across nine Indiana cities.
While the findings are still in early stages, scientists say they offer a promising glimpse of future possibilities. Alzheimer’s disease remains one of medicine’s greatest challenges, with no cure and limited treatment options. Discoveries like this, however, suggest that new strategies — especially those targeting precise biological mechanisms — could gradually transform the landscape of care.
For families affected by Alzheimer’s, even incremental advances carry enormous significance. Each new insight into how the disease works brings researchers closer to therapies that not only slow its progression but potentially protect the brain long before symptoms begin.
