Apolipoprotein E (APOE), one of the primary lipoproteins in the brain has three isoforms in humans – APOE2, APOE3, and APOE4. APOE4 is the most well-established risk factor increasing the pre-disposition for Alzheimer's disease. The presence of the APOE4 allele alone is shown to cause synaptic defects in neurons and recent studies have identified multiple pathways directly influenced by APOE4. However, the mechanisms underlying APOE4 induced synaptic dysfunction remain elusive. Here, we report that the acute exposure of primary cortical neurons or synaptoneurosomes to APOE4 leads to a significant decrease in global protein synthesis. Primary cortical neurons were derived from male and female embryos of Sprague-Dawley rats or C57BL/6J mice. Synaptoneurosomes were prepared from P30 male Sprague-Dawley rats. APOE4 treatment also abrogates the NMDA mediated translation response indicating an alteration of synaptic signaling. Importantly, we demonstrate that both APOE3 and APOE4 generate a distinct translation ...