SENS (Lifespan Research Institute) News

APOE4 Increases Neurons’ Excitability Before Symptoms Appear

The study published in Nature Aging shows that mice carrying the human APOE4 allele develop smaller, hyperexcitable CA3 hippocampal neurons long before any cognitive symptoms appear. Early interictal spike rates in young APOE4 knock‑in mice forecast spatial learning deficits observed months later, linking neuronal hyperexcitability to later Alzheimer’s‑type decline. Deleting APOE4 from neurons, but not astrocytes, normalizes neuron size and firing, and CRISPRi knock‑down of the gene Nell2 reproduces this rescue. These findings suggest a reversible, cell‑type‑specific mechanism that could be targeted for early intervention.