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. 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. 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.
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