Scientists at Indiana University School of Medicine have uncovered a promising new therapeutic target for Alzheimer’s disease, offering a potential fresh direction for treatment development. Their research shows that removing a specific enzyme from neurons in the brain can dramatically reduce amyloid plaques, one of the defining pathological features of the disease. Beyond lowering plaque levels, this approach may also strengthen the brain’s resilience to ongoing neurodegeneration, raising hope for more durable clinical benefits.
In recent years, progress in Alzheimer’s treatment has begun to accelerate. The U.S. Food and Drug Administration has approved two disease-modifying therapies, lecanemab and donanemab, which work by clearing amyloid plaques from the brain. These drugs have shown that it is possible to slow disease progression and stabilise patients at their current level of function. However, their effects are limited, and there remains an urgent need for alternative strategies that target the disease through different biological mechanisms.
The Indiana University team, led by Hande Karahan and Jungsu Kim, focused on an enzyme known as IDOL. Their findings suggest that suppressing IDOL specifically in neurons offers a new way to reduce amyloid accumulation while also improving communication between brain cells and regulating lipid metabolism. According to the researchers, this dual effect could be particularly valuable, as Alzheimer’s disrupts not only protein clearance but also fundamental cellular signalling and metabolic balance in the brain.
Kim emphasised that the appeal of IDOL lies in its suitability as a drug target. Enzymes have clearly defined active sites, which makes it possible to design highly specific molecules that block their activity. This precision increases the likelihood of developing treatments that are both effective and associated with fewer side effects. The identification of IDOL, therefore, opens the door to an entirely new class of therapeutic compounds aimed at Alzheimer’s disease.
To explore how IDOL functions in different brain cell types, the researchers created two animal models of Alzheimer’s disease. In one, the IDOL gene was deleted from neurons, while in the other, it was removed from microglia, the brain’s immune cells. The team initially expected microglia to play the dominant role in clearing amyloid, as immune cells are known to be heavily involved in plaque removal and are the primary producers of IDOL in the brain.
Unexpectedly, the most striking effects were seen when IDOL was removed from neurons. This intervention not only reduced amyloid plaques but also lowered levels of apolipoprotein E, a protein strongly linked to Alzheimer’s risk and disease progression. In addition, receptors involved in lipid metabolism and healthy neuronal communication increased in abundance, suggesting broader protective effects. Previous research has shown that activating related pathways can help preserve cognitive function even in patients with high plaque burdens.
From a clinical perspective, these findings are especially significant. Most patients are diagnosed only after substantial amyloid accumulation has already occurred. An approach that both lowers amyloid levels and enhances the brain’s resilience to existing pathology could therefore maximise therapeutic impact. Looking ahead, Kim and his colleagues plan to develop and test compounds that inhibit IDOL, carefully assessing their safety and effects in preclinical models. They will also investigate whether targeting this enzyme can preserve synaptic connections and reduce tau pathology, two critical factors in the progression of Alzheimer’s disease.
More information: Hande Karahan et al, Deletion of neuronal Idol ameliorates Alzheimer’s disease–related pathologies via APOE receptors, Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. DOI: 10.1002/alz.70949
Journal information: Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association Provided by Indiana University
