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Getting the latest healthcare news for you
Getting the latest healthcare news for you
Your Alzheimer's risk gene may be rewiring your brain decades early. Researchers at Gladstone Institutes found that APOE4 — carried by roughly 1 in 4 people — boosts a protein called Nell2, which shrinks neurons and makes memory circuits hyperactive long before symptoms appear. The good news? Dialing down Nell2 in adult mice reversed the damage, hinting at a potential new treatment window.
A new study from Gladstone Institutes has mapped out, for the first time, exactly how the APOE4 gene variant begins disrupting brain function well before Alzheimer's symptoms emerge. Published in Nature Aging, the research shows that APOE4 ramps up production of a protein called Nell2, which causes neurons to shrink and become overactive — particularly in the hippocampus, the brain's memory hub. Crucially, the degree of that early hyperactivity in young mice predicted how severe their memory problems would be later in life.
The team also made a surprising discovery: the neuronal damage was driven by APOE4 produced within neurons themselves, not by the surrounding support cells (astrocytes) as previously assumed. When researchers used CRISPRi to reduce Nell2 levels in adult APOE4 mice, neurons returned to normal size and firing behavior — suggesting the damage isn't permanent and that intervention may be possible even after disease processes have begun.
By the Numbers
Why it matters: This research opens a potential new therapeutic avenue — targeting Nell2 — that could help the millions of APOE4 carriers reduce their Alzheimer's risk before symptoms ever appear.
