Scientists have uncovered an early brain mechanism that may help explain why people carrying the APOE4 gene face a higher risk of Alzheimer’s disease.
For millions of people who carry the APOE4 gene, the strongest known genetic risk factor for Alzheimer’s disease, changes in brain activity may start years before memory problems become noticeable. Researchers at Gladstone Institutes have now mapped out a series of molecular events that may explain these early brain changes and identified a possible way to reverse them.
In a study published in Nature Aging, scientists used mouse models to show that APOE4 increases production of a protein called Nell2. Elevated Nell2 levels caused neurons to shrink and become unusually overactive. Mice with greater neuron hyperactivity early in life later developed more severe memory problems.
When researchers reduced Nell2 production, neurons returned to a more normal size and activity pattern, even in adult mice carrying APOE4. The findings suggest that drugs targeting Nell2 could one day help lower Alzheimer’s risk in people with the APOE4 gene.
“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.”
