APOE4 is the strongest common genetic risk factor for Alzheimer's disease, yet it is still something of a mystery. The team reports the work September 24 in Cell. The scarring may also feed the buildup of amyloid-beta, a protein thought to be among the first signs of the disease in the brain.
Blanchard says that in a room of 10 people with Alzheimer's, six would carry APOE4. Still, many carriers never develop the disease.
One clue came in 2024, when researchers examined more than 3,500 people. Some carried two copies of APOE4 and had no Alzheimer's. They shared a mutation that left their blood vessels with far lower levels of fibronectin, a cellular superglue that assists wound healing.
Researchers suggested too much fibronectin could make it harder for the brain to clear amyloid-beta. That pushed Blanchard's team to look closer 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. The new work suggests the gene variant may change those vessels directly.