Apolipoprotein E-e4 (APOE4, gene; apoE4, protein) is a susceptibility gene or risk factor for Alzheimer disease. The APOE4 allele frequency is highly significantly increased in affected individuals. The inheritance of APOE4 is associated with increased risk of disease expression at a younger age of onset in a dose-dependent manner. The effect of the more uncommon allele, APOE2, is to decrease the risk and increase the age of onset compared to the common allele APOE3. Thus the effect of inheriting specific alleles of APOE is associated with regulating the rate of expression of Alzheimer disease. Immunoelectron microscopic studies have clearly localized apoE in the cytoplasm of neurons. Based on experimental data, we have suggested that apoE3 (and/or apoE2) plays a protective role by binding and sequestering free tau, perhaps by decreasing the rate of paired helical filament formation or by facilitating microtubule stabilization.