A major Alzheimer’s risk gene may shrink brain cells years before symptoms

Millions of people carry APOE4, the strongest known genetic risk factor for Alzheimer's disease. New research suggests the gene variant may begin altering brain activity well before memory problems become noticeable.

Researchers at Gladstone Institutes have now mapped out a molecular sequence that could help explain these early effects. Their findings also point to a possible way to reverse some of the changes.

In a study using mouse models, published in Nature Aging, the researchers found that APOE4 increases production of a protein called Nell2. Higher Nell2 levels caused neurons to become smaller and unusually active. Mice with the greatest brain hyperactivity when they were young later developed the most severe memory problems.

The team then reduced Nell2 production. Even in adult mice carrying APOE4, neurons returned toward their normal size and firing behavior. The result raises the possibility that future drugs targeting Nell2 could help people with APOE4 who face an elevated risk of Alzheimer's disease.