A gene variant called APOE4 significantly increases the risk of late-onset Alzheimer’s disease, the most common form of dementia. Now, new research reveals the true role of APOE4 in this disease, and a new study identifies a possible way to treat it.
Historically, scientists who study Alzheimer’s disease focused on two proteins that accumulate in patients’ brains: beta-amyloid and tau protein. However, there is a “third thing that people haven’t paid attention to until recently,” said the study co-author. Li Huei Tsaineuroscientist at MIT. That third thing is the buildup of fat droplets, or lipids, in the brain, she told Live Science.
The APOE gene makes proteins responsible for transporting fats around cells in the body and brain. A version of the gene called APOE4, which increases the risk of late-onset Alzheimer’s disease by three to 12 times, produces proteins that are less effective in this function, Tsai said. But how APOE4 affects different brain cells is not clearly understood.
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Tsai’s team has been working to close this gap for about a decade.
“APOE4 can influence many different cell types,” she pointed out. “It’s not just one type of cell.”
Focus on clues
In previous laboratory research, Tsai’s team found that APOE4 causes accumulation cholesterol in astrocytes, star-shaped brain cells that support the function of neurons. Genetic analyzes suggest that the genetic variant could disrupt the way these cells process fat.
Another study focused on oligodendrocytes, cells that help insulate the outgoing wires of neurons with a fatty material called myelin. This material helps neurons send messages more efficiently. APOE4 caused oligodendrocytes to accumulate cholesterol. So, in laboratory mice, the team used a drug to help the cells get rid of this excess cholesterol, which improved the cells’ ability to produce myelin and the mice’s performance on cognitive tests.
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In their latest research, published Thursday October 15 in the journal Stem cellTsai’s team looked at the question of why APOE4 causes fat accumulation in the first place.
They used stem cells to grow oligodendrocytes carrying APOE4, then turned specific genes on or off to see if they increased or decreased fat droplet formation. This screen revealed a major group of genes involved in cell-to-cell communication, called the Wnt signaling pathway. This included a key gene called DKK1, which acts as a brake on this signaling system.
Turning off DKK1 – essentially lifting the brake – reduced the concentration of fat droplets in the cells, the team found.
In brain tissue samples from organ donors with APOE4the team also found signs of low Wnt signaling. This finding “establishes a very strong link” between the signaling pathway and the formation of fat droplets, said Rosie Jacksoncell biologist at the University of Dundee who was not involved in this study.
Myelin (orange) is a fatty material that covers the outgoing wires of many neurons, helping cells send signals more efficiently.
(Image credit: koto_feja via Getty Images)
The effects of APOE4 in the brain
The researchers then investigated exactly how Wnt signaling was disrupted in oligodendrocytes.
APOE4 appears to decrease the supply to cells of a protein that helps relay Wnt signals. This useful protein was broken down by an enzyme whose levels were increased by APOE4. In mice, the team used a drug to block this extra enzyme, and the treatment ultimately restored normal Wnt signaling, reduced fat accumulation, and helped the cells produce myelin properly.
This could change the way scientists think about treating Alzheimer’s disease, Jackson said. This “opens up a new wave of potential therapies” that could target accumulated fat, rather than just tackling beta-amyloids and tau proteins, she said.
“I think it’s becoming a very common idea in the field: We’re going to need multiple drugs targeting slightly different things,” she told Live Science. “And targeting lipids will be a very important part of that.”
That said, the results have not yet been confirmed in humans.
“It is very encouraging that facilitating lipid clearance and movement is a potential therapeutic avenue,” said the study co-author. Joel Blanchardneuroscientist at the Icahn School of Medicine at Mount Sinai. The question is how to achieve this safely and effectively in humans, he said.
Blanchard has led other research that highlights APOE4’s effects beyond fat and myelin. The genetic variant may affect the cells that support blood vessels in the brain by causing scarring and contributing to the accumulation of beta-amyloid. This can also playing with the “waste collectors” inside astrocytesagain leading to a build-up of harmful proteins.
While cells with other versions of the APOE gene can devote a lot of energy to breaking down proteins, cells carrying APOE4 devote all their energy to storing fat, Blanchard said.
But more research is needed to understand how to solve the problem, he said. Hopefully, targeting fat storage “could save not just one thing, but multiple things that go wrong in Alzheimer’s disease,” he told Live Science.
This article is for informational purposes only and is not intended to offer medical advice.
Akay, LA, Bright, A., Dong, D., Smith, ED, Hurt, RC, Boix, CA, Louderback, K., Medrano, J., Sun, D., Lin, H., King, O., Welch, GM, Nawaid, H., Agbas, E., Jiang, A., Bubnys, A., Cheng, J., Blanchard, JW, & Tsai, L. (2026). Genome-wide CRISPR screen reveals that Wnt signaling regulates lipid accumulation in APOE4 oligodendrocytes. Stem cell. https://doi.org/10.1016/j.stem.2026.09.012
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