APOE4 is the strongest common genetic risk factor for Alzheimer’s disease, and its damage is still being mapped. Li-Huei Tsai’s lab at MIT, with lead author Leyla Akay, found one route. In oligodendrocytes, the cells that wrap neurons in insulating myelin, APOE4 shuts down a pathway called Wnt signaling. The cells end up with less beta-catenin and more of a blocking protein, GSK3b. Starved of the signal, they hoard fat in droplets instead of building myelin. The team ran a genome-wide CRISPR screen in human stem-cell-derived oligodendrocytes to find the defect. Then they fixed it. Blocking GSK3b restored myelin in human cells, in 3D brain organoids, and in mice carrying APOE4 and Alzheimer’s-related tau. It is preclinical work, so no patient has benefited yet. Still, myelin is an underrated part of this disease. A drug target already familiar from other fields makes this one worth following.
Source: Cell Stem Cell, October 2026
