Alzheimer's disease (AD) is associated with genetic risk factors, of which the allele E4 of apolipoprotein E (apoE4) is the most prevalent, and is affected by environmental factors that include education early in life and socioeconomic background. The extent to which environmental factors affect the phenotypic expression of the AD genetic risk factors is not known. Here we show that the neuronal and cognitive stimulations, which are elicited by environmental enrichment at a young age, are markedly affected by the apoE genotype. Accordingly, exposure to an enriched environment of young mice transgenic for human apoE3, which is the benign AD apoE allele, resulted in improved learning and memory, whereas mice transgenic for human apoE4 were unaffected by the enriched environment and their learning and memory were similar to those of the nonenriched apoE3 transgenic mice. These cognitive effects were associated with higher hippocampal levels of the presynaptic protein synaptophysin and of NGF in apoE3 but not apoE4 transgenic mice. In contrast, cortical synaptophysin and NGF levels of the apoE3 and apoE4 transgenic mice were similarly elevated by environmental enrichment. These findings show that apoE4 impairs hippocampal plasticity and isoform-specifically blocks the environmental stimulation of synaptogenesis and memory. This provides a novel mechanism by which environmental factors can modulate the function and phenotypic expression of the apoE genotype.