Health

Alzheimer's risk gene APOE4 tied to early brain cell shrinkage and hyperactivity in mice

A study in mice suggests the APOE4 gene variant boosts the protein Nell2, shrinking neurons long before cognitive symptoms emerge.

Updated Aug 24, 2026 · 00:17 UTC1 reports

The short version

Researchers at Gladstone Institutes identified a mechanism where the APOE4 gene variant elevates Nell2 protein levels in mouse neurons, causing cells to shrink and become hyperactive.
The severity of early brain cell hyperactivity in young mice directly predicted worse memory test performance later in life.
Lowering Nell2 expression with CRISPRi or removing neuronal APOE4 reversed the cellular abnormalities in adult mice.
Scientists are investigating whether targeting Nell2 could eventually serve as an early therapeutic strategy for human APOE4 carriers.

A Gladstone Institutes study published in Nature Aging found that the APOE4 gene variant increases the production of Nell2 in mouse hippocampal neurons.[ScienceDaily]
Elevated Nell2 caused hippocampal neurons to shrink and fire excessively, an effect driven by APOE4 within neurons rather than astrocytes.[ScienceDaily]
The degree of early neuronal hyperactivity in young mice correlated with worse spatial learning and memory outcomes as the animals aged.[ScienceDaily]
Using CRISPRi to suppress Nell2 in adult APOE4 mice restored neurons toward their normal size and firing rates.[ScienceDaily]
The APOE4 variant is carried by roughly one in four people and is present in an estimated 60 to 75 percent of Alzheimer's patients.[ScienceDaily]

It remains unproven whether therapies targeting Nell2 can successfully and safely prevent or reverse Alzheimer's disease progression in humans.[ScienceDaily]