APOE4 May Drive Alzheimer’s Risk by Disrupting Fat Processing in Brain Cells

APOE4 may raise Alzheimer’s risk partly by disrupting how brain cells handle fat. A new study traces that buildup to weakened Wnt signaling in oligodendrocytes, the cells that make myelin, and suggests a potential treatment route that differs from targeting amyloid-beta and tau.

The APOE gene helps transport fats through cells in the brain and body. Its APOE4 variant is associated with a three- to 12-fold increase in the risk of late-onset Alzheimer’s disease. Researchers have long focused on amyloid-beta and tau, but MIT neuroscientist Li-Huei Tsai says lipid droplets in brain cells are another part of the disease process that has received less attention.

Tsai’s team has spent about a decade examining how APOE4 affects different cell types. Earlier work found cholesterol buildup in astrocytes, which support neurons. Separate research found excess cholesterol in oligodendrocytes, which wrap neurons’ outgoing fibers in myelin. In mice, helping oligodendrocytes clear cholesterol improved myelin production and performance on cognitive tests.

Tracing fat buildup to Wnt signaling

For the latest study, published Oct. 15 in Cell Stem Cell, the team used stem cells to grow oligodendrocytes carrying APOE4. By switching genes on and off, the researchers searched for changes that affected the formation of fat droplets.

The screen pointed to the Wnt signaling pathway, which helps cells communicate. It also highlighted DKK1, a gene that acts as a brake on Wnt signaling. When researchers disabled DKK1, fat droplets in the cells decreased.

The team also examined brain tissue from organ donors with APOE4 and found signs of low Wnt signaling. Rosie Jackson, a cell biologist at the University of Dundee who was not involved in the study, said the results establish a strong link between the pathway and fat droplet formation.

Effects extend beyond one cell type

The researchers then investigated how APOE4 interferes with Wnt signaling. The variant appeared to reduce the supply of a protein that carries Wnt signals. An enzyme whose levels rose with APOE4 was breaking down that protein. In mice, a drug that blocked the enzyme restored Wnt signaling, reduced fat accumulation and helped oligodendrocytes produce myelin normally.

The findings add to evidence that APOE4 affects several kinds of brain cells and processes. Other research led by study co-author Joel Blanchard, a neuroscientist at the Icahn School of Medicine at Mount Sinai, has linked the variant to scarring around brain blood vessels and amyloid-beta buildup. It has also been associated with impaired waste-clearing systems in astrocytes.

Blanchard says cells with other APOE variants can devote more energy to breaking down proteins, while APOE4-carrying cells direct more energy toward storing fat. That imbalance could connect lipid buildup with several problems seen in Alzheimer’s, though researchers still need to work out how to correct it.

A possible target, with human questions ahead

Jackson says the results point toward treatments that address lipid accumulation alongside approaches aimed at amyloid-beta and tau. She expects lipid handling to be an important part of a broader treatment strategy involving multiple targets.

The evidence so far does not show that the approach works in people. Blanchard called lipid clearance and transport an encouraging therapeutic avenue, while stressing that researchers must determine how to influence them safely and effectively in humans.

The next step is to establish whether these cell and mouse findings translate to patients. If they do, targeting fat storage could help address more than one APOE4-related disruption in the brain.