APOE4 variant disrupts myelin production through Wnt signaling in brain cells
A study found that the Alzheimer's-linked APOE4 variant interferes with myelin production in oligodendrocytes by reducing Wnt signaling. Using CRISPR screening in human cells derived from induced pluripotent stem cells, researchers identified increased GSK3B activity as a suppressor of the Wnt pathway. The results could suggest new targets for drugs aimed at fat-processing problems linked to Alzheimer's disease.
Among known genetic contributors to late-onset Alzheimer's, APOE4 carries the greatest risk. Earlier work by Li-Huei Tsai's group linked this variant to oligodendrocytes that accumulate cholesterol abnormally and make defective myelin, the fatty insulation around neurons.
Using iPSC-derived human oligodendrocytes, the team knocked out each protein-coding gene with CRISPR. They found reduced Wnt signaling and elevated GSK3B activity, which restrains that pathway. After-death brain samples from carriers indicated reduced openness of Wnt-related genes to transcription. A GSK3B inhibitor lowered lipid buildup and boosted myelin in cell and mouse models.
If confirmed, these findings may shape future Alzheimer's research by pointing drug developers toward GSK3B and Wnt signaling. People with APOE4—especially those concerned about late-onset Alzheimer's—could eventually benefit from therapies targeting lipid processing in oligodendrocytes. However, the work remains early-stage, so any clinical impact is uncertain and likely years away. Families, caregivers, and health systems may watch for follow-up studies that test safety and effectiveness in humans.