APOE4 Shrinks Brain Cells Years Before Alzheimer's Symptoms — SkimNews
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- Gladstone Institutes researchers published in Nature Aging showing that APOE4 raises levels of a protein called Nell2, which shrinks neurons and makes hippocampal memory circuits hyperactive in young mice long before memory symptoms appear.
- The degree of hippocampal hyperactivity in young APOE4 mice predicted how poorly they performed on spatial learning and memory tests later in life, tying early circuit changes to later cognitive decline.
- The damaging effect was driven by APOE4 produced inside neurons — not by astrocytes, as previously assumed — since deleting the gene from astrocytes changed nothing, while deleting it from neurons restored normal cell size and firing.
- Using CRISPRi to lower Nell2 in adult APOE4 mice made neurons larger and less excitable, reversing the abnormalities after disease processes had already begun.
- APOE4 is carried by roughly 1 in 4 people and is found in an estimated 60 to 75 percent of Alzheimer's patients, making it the strongest known genetic risk factor for the disease.
- Nell2 had not previously been investigated in connection with APOE4, though earlier research found elevated Nell2 levels in the brains of Alzheimer's patients correlated with poorer cognitive function.
Why it matters: Roughly one in four people carry APOE4, and identifying Nell2 as the molecular driver reframes Alzheimer's risk as a process that begins decades before symptoms. The reversal in adult mice — not just prevention — suggests a drug aimed at Nell2 could intervene even after disease mechanisms are already underway for the millions at highest genetic risk.
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