A new target for Alzheimer’s disease treatment is emerging from research at Indiana University School of Medicine, offering a potentially novel approach to slowing—and perhaps even halting—the progression of this devastating neurological condition. While existing therapies focus on clearing amyloid plaques from the brain, this new research, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, suggests that targeting a specific enzyme, IDOL, could offer a multi-pronged benefit, not only reducing plaque buildup but also bolstering the brain’s natural resilience.
Alzheimer’s disease affects over 55 million people worldwide, according to the World Health Organization, with the disease accounting for 60 to 70 percent of all dementia cases. It’s a progressive illness characterized by memory loss, cognitive decline, and an increasing inability to perform daily tasks. Despite decades of research, current treatments offer only limited symptomatic relief and a slowing of disease progression.
The research team, led by Hande Karahan, PhD, and Jungsu Kim, PhD, discovered that removing the IDOL enzyme from neurons in the brain significantly reduces the formation of amyloid plaques—a hallmark of Alzheimer’s disease. But the benefits don’t stop there. The study also revealed that deleting this enzyme increases the levels of receptors that regulate lipid metabolism, a process that appears to provide cognitive resilience even in the presence of significant plaque buildup.
“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.”
Understanding the Role of IDOL
To understand the potential impact of this discovery, it’s helpful to consider the complex processes occurring in the brain during Alzheimer’s disease. Neurons communicate with each other through connections called synapses. These connections rely on efficient signaling, which can be disrupted by the accumulation of amyloid plaques and other pathological changes. The IDOL enzyme appears to play a role in regulating the number of receptors on the surface of neurons, receptors crucial for receiving and processing these signals.
By controlling the number of these receptors, IDOL influences lipid metabolism, a process vital for maintaining healthy brain function. The researchers found that reducing IDOL activity not only decreased plaque formation but also enhanced the brain’s ability to maintain synaptic connections, even in the face of disease-related damage. This suggests that targeting IDOL could strengthen the brain’s inherent defenses against cognitive decline.
The APOE Connection
The study also uncovered a link between IDOL and apolipoprotein E (APOE), a protein that plays a significant role in lipid transport and is a major genetic risk factor for late-onset Alzheimer’s disease. Specifically, the APOE4 variant significantly increases an individual’s risk of developing the disease. The researchers observed that inhibiting IDOL also lowered levels of APOE in the brain, potentially mitigating the risk associated with this genetic predisposition.
This finding is particularly noteworthy because it suggests that targeting IDOL could address one of the most significant genetic risk factors for Alzheimer’s disease. By reducing APOE levels, the enzyme inhibition may help to prevent or delay the onset of the disease in individuals carrying the APOE4 variant.
Building on Existing Treatments
The U.S. Food and Drug Administration has recently approved two disease-modifying drugs, lecanemab and donanemab, that aim to remove amyloid plaques from the brain. These treatments can “freeze” a person in their current functional state, slowing the progression of cognitive decline. However, they don’t address the underlying mechanisms that contribute to the disease or enhance the brain’s resilience.
The IDOL-targeting approach offers a potentially complementary strategy. While existing drugs focus on clearing existing damage, targeting IDOL aims to prevent plaque formation, protect synaptic connections, and bolster the brain’s natural defenses. This multi-faceted approach could lead to more effective and durable treatment outcomes.
Next Steps and Future Research
The research, conducted in animal models, represents a significant step forward in the search for new Alzheimer’s disease treatments. However, it’s crucial to emphasize that these findings have not yet been replicated in human clinical trials. The next step will be to develop compounds that can safely and effectively inhibit the IDOL enzyme in humans and to evaluate their efficacy in clinical studies.
The precision with which enzymes can be targeted in drug development offers a key advantage. Enzymes possess well-defined active sites, or “pockets,” where drugs can attach and block their activity. This precision allows for the design of molecules that specifically target IDOL with minimal off-target effects.
Researchers are also investigating whether inhibiting IDOL could impact another key protein involved in Alzheimer’s disease: tau. Tau protein abnormalities are closely linked to the progressive neurodegeneration characteristic of the disease. If IDOL inhibition can influence tau pathology, it could further enhance the therapeutic potential of this approach.
While the path to a new Alzheimer’s treatment is long and complex, the discovery of IDOL as a potential drug target offers a renewed sense of hope for the millions of individuals and families affected by this devastating disease. The focus on strengthening the brain’s resilience, rather than solely removing existing damage, represents a promising new direction in Alzheimer’s research.
