Scientists are starting to unravel the most important genetic risk factor for Alzheimer’s

A gene variant called APOE4 dramatically increases the risk of late-onset Alzheimer’s disease, the most common form of dementia. Now, emerging research is revealing APOE4’s true role in the condition, and a new study pinpoints a possible way to treat it.

Historically, scientists studying Alzheimer’s disease have focused on two proteins that accumulate in patients’ brains: amyloid-beta and tau. However, there’s a “third thing that people didn’t pay attention to, until recently,” said study co-author Li-Huei Tsai, a neuroscientist at MIT. That third thing is the accumulation of droplets of fat, or lipids, in the brain, she told Live Science.

The APOE gene makes proteins responsible for transporting fat around cells throughout the body and brain. A version of the gene called APOE4, which increases the risk of late-onset Alzheimer’s three- to 12-fold, makes proteins that are less efficient at this function, Tsai said. But how APOE4 affects different brain cells was not clearly understood.

Tsai’s team has been working to close that gap for about a decade.

“APOE4 can influence many different cell types,” she emphasized. “It’s not just one cell type.”

Zeroing in on the clues

In past laboratory research, Tsai’s team found that APOE4 causes a buildup of cholesterol in astrocytes, star-shaped brain cells that support the function of neurons. Genetic analyses suggested that the gene variant may mess with how these cells process fat.

Another study zoomed in on oligodendrocytes, cells that help insulate neurons’ outgoing wires with a fatty material called myelin. This material helps neurons send messages more efficiently. APOE4 caused the oligodendrocytes to accumulate cholesterol. So, in lab mice, the team used a drug to help the cells get rid of that extra cholesterol, and it improved the cells’ ability to make myelin and the mice’s performance on cognitive tests.

In their latest research, published Thursday (Oct. 15) in the journal Cell Stem Cell, Tsai’s team dug into the question of why APOE4 causes fat to accumulate in the first place.

They used stem cells to grow APOE4-carrying oligodendrocytes and then turned specific genes on or off, to see if they increased or decreased the formation of fat droplets. This screening pointed to 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.

Disabling 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 APOE4, the team also found signs of low Wnt signaling. This finding “establishes a very strong link” between the signaling pathway and formation of fat droplets, said Rosie Jackson, a cell biologist at the University of Dundee who was not involved in this study.

APOE4’s effects across the brain

The researchers then investigated exactly how Wnt signaling was disrupted in oligodendrocytes.

APOE4 seemed to decrease the cells’ supply of a protein that helps relay Wnt signals. That helpful protein was being broken down by an enzyme whose levels had been boosted by the APOE4. In mice, the team used a drug to block that extra enzyme, and the treatment ultimately restored normal Wnt signaling, reduced fat buildup, and helped the cells make myelin properly.

This could change how scientists think about treating Alzheimer’s disease, Jackson said. It “opens up a new wave of potential therapeutics” that could target the accumulated fats, rather than going after only amyloid-beta and tau, she said.

“I think that this is becoming a really common idea in the field — that we’re going to need multiple medications that target slightly different elements,” she told Live Science. “And targeting lipids will be a really important part of that.”

That said, the findings have not been confirmed in humans yet.

“It’s very encouraging that facilitating lipid clearance and lipid movement is a potential therapeutic avenue,” said study co-author Joel Blanchard, a neuroscientist at the Icahn School of Medicine at Mount Sinai. The question is how we can do that in a safe and effective manner in humans, he said.

Blanchard has led other research that underscores APOE4’s effects beyond fats and myelin. The gene variant may affect cells that support blood vessels in the brain by driving scarring and contributing to amyloid-beta buildup. It may also mess with the “trash collectors” inside astrocytes, again leading to a buildup of harmful proteins.

While cells with other versions of the APOE gene can put a lot of energy toward breaking down the proteins, APOE4-carrying cells put all their energy toward fat storage, Blanchard said.

But more research is needed to understand how to fix the problem, he said. Hopefully, targeting fat storage “could rescue not just one thing but multiple things that go wrong in the course of Alzheimer’s disease,” he told Live Science.