Scientists at Gladstone Institutes have detailed a specific chain of molecular events, beginning in the brain's immune cells, that is triggered by the APOE4 gene variant and leads to the early brain changes characteristic of Alzheimer's disease. The research, published in the journal Nature Aging, explains how APOE4 initiates a harmful cascade in microglial cells long before cognitive symptoms appear.
The study found that the APOE4 protein binds to a receptor on microglia called LILRB4. This binding suppresses the normal activity of these cells, preventing them from properly clearing away a toxic protein called amyloid-beta. This failure in clearance is a key early step in the development of Alzheimer's pathology.
"We've identified a specific pathway that connects the major genetic risk factor for Alzheimer's to the dysfunction of the brain's immune cells," said Dr. Yadong Huang, the senior author of the study. The findings, based on research in human cells and mouse models, offer a new potential target for therapies aimed at interrupting this damaging process early in the disease timeline.
Carrying one copy of the APOE4 gene variant significantly increases a person's risk of developing Alzheimer's, while having two copies makes it the strongest known genetic risk factor. This research provides a mechanistic explanation for how this genetic risk translates into initial biological changes in the brain.
