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

A new study identifies a potential link between the APOE4 gene variant, lipid buildup and impaired myelin production—suggesting a possible new direction for Alzheimer’s treatment research.

A gene variant called APOE4 dramatically increases the risk of late-onset Alzheimer’s disease, the most common form of dementia. New research suggests that APOE4 may contribute to the disease by disrupting how brain cells store and process fats.

Scientists have traditionally focused on two proteins that accumulate in the brains of people with Alzheimer’s: amyloid beta and tau. But researchers are increasingly investigating a third factor—lipid droplets, or microscopic fat deposits that build up inside brain cells.

“APOE4 can affect many different cell types,” said Li-Huei Tsai, a neuroscientist at MIT. “It’s not just one type of cell.”

How APOE4 affects fat transport in the brain

The APOE gene produces a protein that transports fat around cells throughout the body and brain. The APOE4 version of the gene produces a protein that is less efficient at this job.

APOE4 is associated with a three- to 12-fold increase in the risk of late-onset Alzheimer’s disease. However, scientists have not fully understood how the variant affects different types of brain cells.

Tsai’s team has studied this question for about a decade. Earlier laboratory research found that APOE4 causes cholesterol to accumulate in astrocytes, star-shaped cells that support neurons. Genetic analysis also suggested that mutations can change how astrocytes process fat.

Other research found that APOE4 causes oligodendrocytes—cells that produce myelin—to accumulate cholesterol. Myelin is the fatty substance that insulates neurons and helps them send signals efficiently.

In laboratory mice, a drug that helped cells remove excess cholesterol improved their ability to produce myelin and improved the animals’ performance on cognitive tests.

Researchers identify the Wnt signaling pathway

In their latest work, the researchers used stem cells to grow oligodendrocytes carrying APOE4. They then switched specific genes on or off to determine which ones increased or decreased the formation of lipid droplets.

The screening identified the Wnt signaling pathway, a major group of genes involved in communication between cells. It also highlighted a key gene called DKK1, which acts as a brake on Wnt signaling.

When the researchers disabled DKK1 and released that brake, the amount of lipid droplets inside the cells decreased.

In brain tissue samples from organ donors with APOE4, the team also found signs that Wnt signaling was reduced. Rosie Jackson, a cell biologist at the University of Dundee who was not involved in the study, said the findings establish a strong link between Wnt signaling and lipid-droplet formation.

How APOE4 may affect myelin and brain health

The researchers then investigated how APOE4 disrupts Wnt signaling in oligodendrocytes.

They found that APOE4 appears to reduce the cellular supply of proteins needed to relay Wnt signals. An enzyme whose levels were increased by APOE4 broke down one of those proteins. In mice, a drug that blocked the excess enzyme restored more normal Wnt signaling, reduced fat storage and helped oligodendrocytes produce myelin properly.

The findings could broaden the way scientists think about Alzheimer’s disease treatments. Instead of targeting only amyloid beta and tau, future therapies might also target abnormal fat storage and lipid metabolism in the brain.

“Targeting lipids is going to be a really important part” of developing multiple treatments for Alzheimer’s disease, Jackson said.

Could targeting fat deposits lead to an Alzheimer’s treatment?

The research has not yet been confirmed in humans, and no treatment based on these findings is currently established.

“It is very encouraging that promoting lipid clearance and lipid mobilization is a potential therapeutic avenue,” said Joel Blanchard, a neuroscientist at the Icahn School of Medicine at Mount Sinai. The challenge, he said, is finding a way to target the process safely and effectively in people.

Blanchard’s research has also highlighted effects of APOE4 beyond fat storage and myelin. The variant can affect cells that support blood vessels, promote scarring, contribute to amyloid beta accumulation and disrupt the brain’s cellular waste-clearance systems.

Compared with cells carrying other APOE variants, cells with APOE4 may devote more energy to storing fat and less energy to breaking down proteins, Blanchard said.

More research is needed to determine whether targeting lipid deposits could address several problems involved in Alzheimer’s disease progression. Researchers hope that improving fat clearance might eventually help rescue multiple types of brain-cell dysfunction.

Study reference: Akey, L. A., et al. (2026). “Genome-wide CRISPR screen reveals that Wnt signaling regulates lipid accumulation in APOE4 oligodendrocytes.” Cell Stem Cell.