Although apolipoprotein (apo) E4 is present in amyloid plaques and neurofibrillary tangles, its pathogenic role in Alzheimer's disease (AD) is unclear. Neuronal expression of apoE4 or apoE4 fragments in transgenic mice increases tau phosphorylation. To identify the kinase responsible for the increase, we studied transgenic mice expressing human apoE3 or apoE4 in neurons under the control of the neuron-specific enolase promoter. Brain levels of phosphorylated tau (p-tau) and phosphorylated (active) extracellular signal-regulated kinase (p-Erk) increased with age in both groups but were considerably higher in the apoE4 mice. Other candidate kinases, including glycogen synthase kinase 3beta and cyclin-dependent kinase-5 and its activators p25 and p35, were not significantly altered. The increases in p-Erk and p-tau were highest in the hippocampus, intermediate in the cortex, and lowest in the cerebellum. In the hippocampus, p-Erk and p-tau accumulated in the hilus and CA3 region of the dentate gyrus, where high levels of zinc are found along mossy fibers. In Neuro-2a cells stably expressing apoE3 or apoE4, treatment with ZnCl2 generated 2-fold more p-Erk and 3-fold more p-tau in the apoE4-expressing cells. Phosphorylation of Erk and tau was reduced by preincubation with the Erk pathway inhibitor U0126. Thus, increased tau phosphorylation in apoE4 transgenic mice was associated with Erk activation and could be modified by zinc, suggesting that apoE4 and zinc act in concert to contribute to the pathogenesis of AD.