Scarred blood vessels may be one clue to APOE4’s Alzheimer’s risk

The gene APOE4 is the strongest common genetic risk factor for Alzheimer’s disease. But it’s still something of a mystery to researchers.

Now, new work suggests one way the gene variant does its dirty work. It influences the production of scar tissue throughout vital vascular connections carrying blood to and from the brain, researchers report September 24 in Cell. This process may also contribute to the buildup of the protein amyloid-beta, which is thought to be one of the first signs of Alzheimer’s disease in the brain.

APOE4 is an allele, one of three slightly different, common forms of the APOE gene, which makes a protein that helps carry fats in the bloodstream. The variant is common among people who have Alzheimer’s disease. “If you had a room of 10 people with Alzheimer’s disease, and you asked how many of those people have the APOE4 allele, six of them would,” says neuroscientist Joel Blanchard of the Icahn School of Medicine at Mount Sinai in New York City. Yet many people who carry APOE4 never develop the dementia-causing disease, leaving researchers trying to understand what the gene variant actually does to make the brain more vulnerable.

One clue came from people who seemed unusually resilient to that risk. In 2024, researchers examined more than 3,500 people, including some who carried two copies of APOE4 but had not developed Alzheimer’s. Genetic analysis showed that they had a mutation in their DNA that meant their blood vessels had far lower levels of a protein called fibronectin, a kind of cellular superglue that assists wound healing. The reserachers suggested that too much fibronectin could make it harder for the brain to clear amyloid-beta from the brain. A buildup of those plaques is a hallmark of the disease.

That result pushed Blanchard and his colleagues to look more closely at blood vessels. “The prevailing thought in the field is basically that the Alzheimer’s disease is so bad that the blood vessels break down,” Blanchard says. ”But we wanted to ask the question: Is it the other way around?”

Blanchard and his colleagues built an atlas that mapped gene expression — how DNA is read and converted into proteins — across the human brain vasculature at a cellular level. Stitching together data from three existing brainwide maps, their atlas represented 66,000 cells from 220 people. They team examined how this map differed in people with two copies of APOE4 compared with those with less harmful gene variants.

 APOE4 carriers had fewer pericytes, starfish-shaped cells that wrap around and stabilize blood vessels. They also had higher numbers of myofibroblasts, cells normally formed during tissue injury that pump out fibronectin, the team found.

The map offered a snapshot, but it couldn’t show whether the missing pericytes were actually transforming into myofibroblasts. The researchers turned to 3-D models of human brain tissue grown from stem cells. In models carrying two copies of APOE4, pericytes began taking on the characteristics of scar-producing myofibroblasts. The transformation also offered a possible explanation for the earlier clue from resilient APOE4 carriers: Myofibroblasts produce large amounts of fibronectin. And when the researchers prevented cells in their models from producing fibronectin, amyloid accumulation dropped.

The researchers also found a possible trigger for the cellular switch. In the APOE4 models, signaling through the immune molecule TGF-beta helped drive pericytes toward the scar-producing state. Blocking that signaling in cell models and aged mice restored the proportion of blood vessels wrapped up by pericytes.

The TGF-beta data are “particularly interesting,” because inhibiting the protein reversed some of APOE4’s effects on pericytes, says Abdel Ali Belaidi, a neuroscientist at the Florey Institute of Neuroscience and Mental Health in Parkville, Australia. But TGF-beta performs many jobs throughout the body, he says, making it a difficult molecule to target safely with a drug.

And damage to the brain’s blood vessels is only one of the many ways APOE4 has been linked to Alzheimer’s. Other studies have shown that the gene variant alters inflammation and interacts with another Alzheimer’s-linked protein, tau. How all these changes lock together to link APOE4 so strongly to Alzheimer’s disease is a greater mystery than one study can solve. ”As a field, we’re all progressing toward an answer,” Blanchard says.