APOE4, the most common genetic risk factor for late-onset Alzheimer’s, may begin harming the brain far earlier than thought — shrinking neurons and making them abnormally excitable years before any memory problems appear.
Researchers at the Gladstone Institutes found that in mice carrying APOE4, the variant drives up levels of a protein called Nell2 specifically inside neurons (not their supporting astrocytes). Elevated Nell2 made the neurons smaller and more electrically excitable, and this early hyperactivity in the hippocampus — the brain’s memory hub — predicted later cognitive decline. The findings appeared in Nature Aging (2026).
A reversible process?
Crucially, reducing Nell2 in adult mice reversed these changes. “We found fundamental changes in brain circuits occurring in young mice that still had normal learning and memory,” said Gladstone’s Misha Zilberter. Senior author Yadong Huang added that “APOE4 accelerates a process that resembles normal aging,” and stressed that “the damage is not irreversible, and that there may be a window for intervention even after disease processes have been triggered.”
Why it matters
People who carry APOE4 are more likely to develop Alzheimer’s, often earlier — but why has been unclear. Identifying an early, potentially reversible mechanism, and a specific protein behind it, points to possible new targets and a treatment window before symptoms begin. This is preclinical mouse research; whether reducing Nell2 helps people would need to be tested. This article summarizes early research and is not medical advice.