Researchers have uncovered a possible reason why the Alzheimer’s risk gene APOE4 can disrupt the brain long before memory problems begin. In mice, APOE4 increased a protein called Nell2, shrinking neurons and making memory circuits unusually active. That early hyperactivity predicted worse memory later in life. Reducing Nell2 in adult mice reversed the abnormal changes, raising hopes for a new way to intervene before Alzheimer’s progresses.
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.
“To the best of our knowledge, this is the first study that has directly examined what APOE4 does to the function of neurons at different ages,” says Misha Zilberter, PhD, principal staff research scientist at Gladstone and a senior author of the study. “We found fundamental changes in brain circuits occurring in young mice that still had normal learning and memory, and importantly, that those changes predicted the development of cognitive deficits at older ages.”
https://www.sciencedaily.com/releases/2026/08/260821012234.htm
