A major Alzheimer’s risk gene may shrink brain cells years before symptoms
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- Gladstone Institutes researchers found that the APOE4 Alzheimer's risk gene boosts production of a protein called Nell2, causing hippocampal neurons to shrink and become hyperactive in young mice well before any memory deficits appeared.
- The extent of hippocampal hyperactivity in young APOE4 mice predicted how poorly those animals later performed on spatial learning and memory tests, the team reports in Nature Aging.
- Deleting APOE4 from neurons — but not from astrocytes, the brain cells that produce most APOE — restored neurons to normal size and firing patterns, identifying neuronal APOE4 as the key driver.
- Scientists then used CRISPRi, a method that dials down a gene without editing DNA, to lower Nell2 in adult APOE4 mice, and the neurons returned toward normal size and became less excitable.
- Roughly one in four people carry APOE4, and the variant is estimated to occur in 60 to 75 percent of people with Alzheimer's disease, underscoring the population that could benefit from a Nell2-targeted drug.
Why it matters: The work gives drug developers a concrete, druggable target downstream of APOE4 rather than the hard-to-drug gene itself. Because lowering Nell2 reversed damage in adult mice — not just prevented it — researchers now have a candidate intervention window for the roughly 25% of people who carry APOE4, a group disproportionately represented among Alzheimer's patients.
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