The allele E4 of apolipoprotein E4 (apoE4), which is the most prevalent genetic risk factor of Alzheimer's disease (AD), inhibits synaptogenesis and neurogenesis and stimulates apoptosis in brains of apoE4 transgenic mice that have been exposed to an enriched environment. In the present study, we investigated the hypothesis that the brain activity-dependent impairments in neuronal plasticity, induced by apoE4, are mediated via the amyloid cascade. Importantly, we found that exposure of mice transgenic for either apoE4, or the Alzheimer's disease benign allele apoE3, to an enriched environment elevates similarly the hippocampal levels of amyloid-beta peptide (Abeta) and apoE of these mice, but that the degree of aggregation and spatial distribution of Abeta in these mice are markedly affected by the apoE genotype. Accordingly, environmental stimulation triggered the formation of extracellular plaque-like Abeta deposits and the accumulation of intra-neuronal oligomerized Abeta specifically in brains of apoE4 mice. Further experiments revealed that hippocampal dentate gyrus neurons are particularly susceptible to apoE4 and environmental stimulation and that these neurons are specifically enriched in both oligomerized Abeta and apoE. These findings show that the impairments in neuroplasticity which are induced by apoE4 following environmental stimulation are associated with the accumulation of intraneuronal Abeta and suggest that oligomerized Abeta mediates the synergistic pathological effects of apoE4 and environmental stimulation.