APOE and neurodegenerative disease: We demonstrate that the removal of neuronal APOE4 has wide-ranging beneficial effects, leading to drastic reductions (1) in the accumulation and spread of pathological tau throughout the hippocampus; (2) in neurodegeneration and hippocampal neuron loss; (3) in myelin deficits and depletion of oligodendrocytes and OPCs; (4) in neuronal network hyperexcitability; (5) in microgliosis and astrogliosis and (6) in the accumulation of neurodegenerative disease-associated cell subpopulations.