Ezetimibe, a cholesterol-lowering medication, has been identified as a potential neuroprotective agent that significantly reduces the risk of Alzheimer's disease and related dementias (ADRD). The research focused on the interaction between the 14-3-3G protein and hexokinase-1 (HK1), proteins that are found in elevated levels in both heart disease and ADRD patient brain aggregates. The study demonstrated that ezetimibe disrupts this protein-protein interaction, reducing protein aggregation, a hallmark of Alzheimer's and other neurodegenerative diseases. Through high-resolution proteomics and cultured cell models, the research team found that ezetimibe potently reduces aggregation and improves cellular function. In experiments with human cells and model organisms, the drug consistently decreased aggregate accumulation and even improved autophagy, the process by which cells remove damaged components.

Additionally, this research identified a sevenfold reduction in the likelihood of developing ADRD among patients treated with ezetimibe. The drug's effect was particularly pronounced in individuals with a history of coronary artery disease, where ezetimibe reduced their risk of ADRD by more than eightfold. Clinical database analyses supported the mechanistic findings, confirming that patients who received ezetimibe experienced a significantly lower incidence of dementia compared to untreated individuals. These results were consistent across different populations, further suggesting that ezetimibe's neuroprotective properties may extend beyond its cholesterol-lowering effects, making it a promising candidate for repurposing as a dementia-prevention therapy.

This study not only introduces a novel mechanism through which ezetimibe can protect against neurodegenerative diseases but also provides compelling evidence that protein aggregation and neuroinflammation are critical targets for therapeutic intervention. Ezetimibe's ability to disrupt pathological protein interactions and promote autophagy positions it as a potentially transformative treatment for individuals at high risk for Alzheimer's, especially those with cardiovascular comorbidities. Future studies are warranted to optimize dosing and explore long-term outcomes, but this research lays a strong foundation for the use of ezetimibe in preventative brain health strategies.