APOE4 Study Identifies Possible Early Pathway to Alzheimer’s
New research from Gladstone Institutes suggests that APOE4, the strongest known genetic risk factor for Alzheimer’s disease, may alter brain function long before memory symptoms emerge. The study, conducted in mice and published in Nature Aging, identifies a protein called Nell2 as a possible driver of these early changes and a potential target for future treatments.
About one in four people carries APOE4, which is found in an estimated 60 to 75 percent of people with Alzheimer’s. Researchers examined neurons in the hippocampus, a brain region involved in memory, and found that young mice carrying APOE4 had smaller, unusually active neurons. The degree of early hyperactivity predicted the severity of learning and memory problems later in life.
Mice carrying APOE3, a gene variant associated with lower Alzheimer’s risk, developed similar neuronal excitability only in old age. The researchers said this pattern suggests that APOE4 may accelerate a process resembling normal aging.
The study also found that the changes were driven by APOE4 produced inside neurons, rather than by APOE4 produced in astrocytes, the support cells that generate most of the protein in a healthy brain. Removing APOE4 from neurons restored more typical cell size and activity.
Further analysis identified elevated Nell2 levels in APOE4 neurons. Using CRISPR interference, a technique that reduces gene activity without permanently altering DNA, researchers lowered Nell2 production in adult mice. Their neurons subsequently became larger and less excitable.
The findings indicate that some APOE4-related changes may be reversible, even after they have begun. However, the research was conducted in mouse models, and additional studies will be needed to determine whether Nell2 has the same role in humans and whether safely targeting it can reduce Alzheimer’s risk or delay cognitive decline in people who carry the variant. Human trials would still be necessary before clinical use.