APOE4 Gene Impairs Myelination but GSK3b Inhibitor Restores It

The APOE4 variant, the strongest genetic risk factor for late‑onset Alzheimer’s disease, weakens a key brain‑cell pathway called Wnt signaling in oligodendrocytes, the cells that wrap neurons with fatty myelin. A genome‑wide CRISPR knockout screen and chromatin‑accessibility mapping in human induced pluripotent stem‑cell–derived oligodendrocytes showed that loss of Wnt activity leads to lipid droplets accumulating inside the cells and prevents proper myelin formation. The same pattern was seen in post‑mortem human brain tissue, confirming that APOE4 carriers have fewer Wnt‑responsive genes expressed. These findings explain how the gene variant can damage the brain’s white‑matter wiring beyond its known effects on amyloid or inflammation.

By targeting the pathway that is suppressed, the team showed that a small‑molecule inhibitor of the kinase GSK3b, called CHIR99021, can reactivate Wnt signaling. In human oligodendrocyte cultures, the drug dissolved the lipid droplets and restored myelin production. When the same inhibitor was applied to three‑dimensional brain organoids containing APOE4 oligodendrocytes and neurons, axon growth and myelination were markedly improved. In mice engineered to carry human APOE4 and Alzheimer’s‑like tau pathology, treated animals had fewer lipid droplets in the hippocampus and increased healthy myelin compared with untreated controls.

The study suggests that the APOE4‑driven lipid dysregulation and impaired myelination may be linked to the same signaling axis that drives tau protein hyperphosphorylation, a hallmark of Alzheimer’s disease. Targeting GSK3b therefore offers a dual therapeutic opportunity: to repair brain insulation and to reduce tau pathology. The investigators have applied for a patent on their CRISPR screen approach and plan to explore the connection between GSK3b activity, lipid metabolism, and tau in future work.