Researchers uncover a chain of molecular events behind early brain changes in Alzheimer's

For the millions of people who carry the gene APOE4, the strongest known genetic risk factor for Alzheimer's disease, their brain activity may begin changing long before any memory problems appear. Now, researchers at Gladstone Institutes have uncovered a precise chain of molecular events behind those early changes and identified a potential way to reverse them.

Published in the journal Nature Aging, their new study in mouse models reveals how APOE4 triggers increased production of the protein Nell2, which makes neurons shrink and become hyperactive. The more hyperactive the neurons were in early life, the more severe were the memory problems the mice developed later in life.

When the researchers reduced the production of Nell2, neurons recovered their normal size and firing patterns-even in adult mice with the APOE4 gene. This points toward the possibility of developing drugs that block Nell2 for human APOE4 carriers at high risk for 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. 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."