Summary: Researchers have identified a promising drug target that could change how Alzheimer’s disease is treated. By inhibiting an enzyme called IDOL in neurons, scientists reported a marked reduction in toxic amyloid plaque accumulation and signs of improved neuronal health.
Unlike existing therapies that mainly clear existing plaques, targeting neuronal IDOL also reduces levels of the APOE protein—a major genetic risk factor for late-onset Alzheimer’s—and enhances pathways that support lipid metabolism and synaptic resilience. This combined effect both reduces pathological burden and strengthens neural communication, offering a more comprehensive strategy to slow disease progression.
Key Facts
- Targeting Neuronal IDOL: Removing the IDOL enzyme from neurons substantially lowers amyloid plaque load and improves signaling between nerve cells.
- Resilience Booster: Deleting IDOL raises levels of receptors that regulate lipid metabolism and neuronal health, mechanisms linked to cognitive resilience even when plaques are present.
- APOE Reduction: Neuronal IDOL removal decreases levels of apolipoprotein E (APOE), including factors related to the APOE4 genetic risk variant for late-onset Alzheimer’s.
Source: Indiana University
Indiana University School of Medicine researchers report a new therapeutic direction for Alzheimer’s disease.
The team discovered that deleting an enzyme called IDOL specifically in neurons significantly reduces amyloid plaques—one of the disease’s defining features—and simultaneously supports biological processes that increase the brain’s resistance to cognitive decline.
Recently approved disease-modifying treatments such as lecanemab and donanemab act by removing amyloid plaques and can stabilize patients’ functional abilities. The IU researchers say the IDOL-targeting approach could complement or extend these benefits by both clearing plaques and strengthening neuronal resilience.
The IU School of Medicine team, led by Hande Karahan, PhD, and Jungsu Kim, PhD, reports that neuronal IDOL inhibition can both reduce amyloid deposition and improve lipid receptor expression and synaptic signaling in the brain.
“What makes this exciting is that we now have a defined molecular target that could lead to a new class of treatments,” said Jungsu Kim, the P. Michael Conneally Professor of Medical and Molecular Genetics.
“Enzymes like IDOL have well-defined active pockets where small molecules can bind, which makes them attractive drug targets. That precision could enable therapies that close the pathological loop with fewer off-target effects.”
In work published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, the group created mouse models of amyloid pathology in which the IDOL gene was selectively deleted either in neurons or in microglia, the brain’s resident immune cells.
Karahan, assistant research professor of medical and molecular genetics, said the team initially expected microglial IDOL to be the dominant influence on amyloid clearance because immune cells typically mediate plaque removal and are a major source of IDOL in the brain.
Surprisingly, deletion of IDOL in neurons—not microglia—produced the strongest effect: reduced amyloid plaque accumulation and lower levels of apolipoprotein E (APOE), a protein closely associated with Alzheimer’s risk. APOE plays a central role in lipid transport and neuronal maintenance; its APOE4 variant is the best-known genetic risk factor for late-onset disease.
The researchers also observed increased expression of receptors that bind APOE and influence amyloid handling when IDOL was removed from neurons. These receptors contribute to healthy lipid metabolism and synaptic function, and they are linked to pathways that support cognitive resilience even in individuals with substantial plaque burden.
“Clinically, this matters because most patients are diagnosed after significant plaque accumulation,” Karahan explained. “A strategy that both lowers plaque levels and strengthens the brain’s resilience could provide greater clinical benefit than plaque removal alone.”
Kim added that the next steps include designing and testing molecules that inhibit IDOL, evaluating their safety and effectiveness in preclinical models, and determining whether IDOL inhibition protects synaptic connections and reduces tau-related pathology.
Key Questions Answered:
A: Current antibody therapies clear existing plaques, which can halt functional decline. Targeting neuronal IDOL offers an additional mechanism: it reduces APOE levels and increases receptors that support lipid metabolism and synaptic health. In short, it both clears pathology and reinforces the brain’s capacity to cope with remaining damage.
A: APOE4 is the most significant genetic risk factor for late-onset Alzheimer’s. The study shows that neuronal IDOL deletion lowers APOE levels, suggesting a way to reduce genetic risk factors while also addressing plaque buildup. Targeting both elements could produce stronger, longer-lasting effects.
A: Potentially. IDOL is an enzyme with a defined binding pocket, making it amenable to small-molecule drug design. Researchers are now working to develop inhibitors that can be tested for safety and efficacy in preclinical and, eventually, clinical studies.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The cited journal paper was reviewed in full.
- Additional context was provided by the publication’s staff.
About this Alzheimer’s disease and neuropharmacology research news
Author: Rory Appleton ([email protected])
Source: Indiana University
Contact: Rory Appleton – Indiana University
Image: The image is credited to Neuroscience News
Original Research: Open access. “Deletion of neuronal Idol ameliorates Alzheimer’s disease–related pathologies via APOE receptors” by Hande Karahan, Kelly Hartigan, Md Mamun Al-Amin, Sutha K. John, Brianne McCord, H. R. Sagara Wijeratne, Dominic J. Acri, Daniel C. Smith, Luke C. Dabin, Hannah M. Rondon Cordero, Byungwook Kim, Do-Hun Lee, Jungsu Kim. Alzheimer’s & Dementia. DOI: 10.1002/alz.70949
Abstract
Deletion of neuronal Idol ameliorates Alzheimer’s disease–related pathologies via APOE receptors
INTRODUCTION
Previous studies show that increasing levels of the low-density lipoprotein receptor (LDLR) lowers apolipoprotein E (APOE) and reduces amyloid beta (Aβ) pathology. IDOL is an enzyme that tags LDLR for degradation. The researchers hypothesized that inhibiting IDOL would preserve endogenous LDLR, thereby reducing APOE levels and attenuating amyloid pathology.
METHODS
To determine how IDOL functions in different brain cell types, the team created conditional Idol knockout mice on an Aβ-amyloidosis background and performed biochemical, histological, and multi-omics analyses to assess molecular and cellular effects.
RESULTS
The study showed that deleting Idol in neurons—but not in microglia—reduced amyloid accumulation and changed levels of brain LDLR and APOE. Neuronal deletion increased receptors involved in synaptic function, such as Reelin receptors, and single-nuclei RNA sequencing revealed transcriptional changes linked to synaptic organization and neuronal communication.
DISCUSSION
These findings indicate that neuronal IDOL plays a central role in Alzheimer’s disease pathogenesis by regulating APOE receptors and related lipid-handling pathways. Targeting neuronal IDOL could therefore provide a dual benefit: lowering amyloid burden while enhancing neuroprotective mechanisms that support cognitive resilience.