New findings from researchers at Columbia University lend sharper clarity to the amyloid hypothesis and point toward a fresh approach for treatment. The work appears in a Science Advances publication.
The team examined brain cells from individuals diagnosed with Alzheimer’s disease and observed a consistent pattern: beta-amyloid protein clumps are present, but the critical factor is the glue that links two other proteins inside neurons, called CREB3L2 and ATF4.
When CREB3L2 and ATF4 pair up, a cascade of other proteins becomes active. This cascade promotes the buildup of tau protein within neurons and disrupts cellular waste clearance mechanisms, both of which contribute to dementia symptoms. The study shows that while CREB3L2 and ATF4 exist separately in healthy neurons, their connection intensifies when amyloid levels rise.
Importantly, the researchers identified dovitinib as a compound that blocks the formation of the CREB3L2 ATF4 pair. Dovitinib has prior FDA approval for treating kidney cancer, but its potential role in addressing Alzheimer’s disease has not yet been tested. The team notes that dovitinib does not appear toxic to neurons and can cross the brain barrier, reaching neural tissue after systemic administration. This opens a potential fast track path for dementia trials. [Attribution: Science Advances study, 2024]
Experts caution that these results do not yet establish a cure or a proven therapy for Alzheimer’s disease. They describe a model in which the amyloid protein acts not simply as a toxic aggregate but as a trigger for a network of protein interactions that shift the brain’s internal environment toward neurodegenerative change. The proposed therapy targets the molecular glue between CREB3L2 and ATF4, aiming to interrupt the downstream events that lead to tau aggregation and impaired protein clearance. Further research will be needed to confirm safety, efficacy, and optimal dosing in humans. [Attribution: Science Advances study, 2024]
In the broader context, these findings align with ongoing efforts to translate molecular insights into practical treatments for Alzheimer’s disease. The discovery adds to a growing set of strategies that seek to modify disease pathways rather than simply removing amyloid deposits. The potential to repurpose an already approved drug for rapid testing in dementia trials presents a notable avenue for accelerating progress while researchers pursue a deeper understanding of how these cellular interactions influence disease progression. [Attribution: Science Advances study, 2024]