Gladstone Institutes Identifies Molecular Chain Linking APOE4 Gene to Early Brain Hyperactivity and Alzheimer’s Risk

New research reveals how the APOE4 gene uses the Nell2 protein to shrink neurons and cause hyperactivity long before Alzheimer’s symptoms appear.

By: AXL Media

Published: Apr 3, 2026, 10:40 AM EDT

Source: Information for this report was sourced from EurekAlert

The Genetic Blueprint of Early Brain Dysfunction

For the millions globally carrying the APOE4 gene variant—the most significant genetic risk factor for Alzheimer’s disease—the path toward cognitive decline may begin far earlier than previously understood. Scientists at Gladstone Institutes have successfully mapped a precise chain of molecular events that disrupt brain circuits long before the first symptoms of memory loss emerge. By studying mouse models, the team discovered that APOE4 causes neurons in the hippocampus to produce abnormally high levels of a protein called Nell2. This overproduction leads to a "double hit" on brain health: neurons physically shrink and simultaneously become hyperactive, firing more readily in response to stimulation. This early-life hyperactivity was found to be a direct predictor of the severity of memory deficits later in life.

Nell2: A New Target for Alzheimer’s Intervention

The identification of Nell2 as a mediator of APOE4-induced damage marks a significant breakthrough in neurodegenerative research. While previous studies have noted elevated Nell2 levels in the brains of deceased Alzheimer’s patients, this research is the first to establish its role as a driver of early circuit dysfunction. Using CRISPRi technology to selectively lower Nell2 expression in adult mice, the researchers observed a remarkable reversal of disease manifestations. Treated neurons returned to their normal size and regained healthy firing patterns. Senior author Yadong Huang, MD, PhD, noted that this finding suggests the damage caused by APOE4 is not irreversible, potentially opening a window for intervention even after the biological processes of the disease have been initiated.

A Shift from Astrocytes to Neuronal APOE4

One of the most surprising revelations of the study is the source of the problematic APOE4 protein. For decades, the scientific consensus held that the majority of APOE4 was produced by astrocytes—star-shaped support cells in the brain—and that these cells were likely responsible for the associated Alzheimer’s risk. However, the Gladstone team found that deleting APOE4 from astrocytes had no effect on neuronal hyperactivity. Instead, the link was entirely mediated by APOE4 produced within the neurons themselves. When the gene was removed specifically from neuronal cells, they grew to a healthy size and functioned normally, p...