How APOE4, the leading late-onset Alzheimer’s risk gene, disrupts myelin
Science & technology · 28 October 2026
APOE4 is the common genetic variant that most strongly increases the risk of late-onset Alzheimer's disease. Earlier work found that oligodendrocytes — cells that wrap axons in electrically insulating myelin — accumulate lipid droplets and myelinate less effectively in APOE4 carriers. The new Picower Institute study investigates the mechanism connecting those effects.
A genome-wide CRISPR screen and DNA-accessibility analysis pointed to reduced Wnt signalling. APOE4 oligodendrocytes had less beta-catenin, which promotes the pathway, and more GSK3b, which suppresses it. Inhibiting GSK3b reduced lipid deposits and restored myelination in human cultures, organoids, and mice modelling APOE4 and tau pathology.
The work provides a therapeutic target and proof of principle, not a treatment for patients. The experimental compounds have not been validated for this use in people, and manipulating a broad cellular pathway may have unwanted effects. Dose, safety, brain delivery, and cognitive benefit require further models and clinical trials.
Source: David Orenstein · Picower Institute.