SORLA is a genetic risk factor in Alzheimer’s disease (AD), but it is unclear how changes in SORLA abundance can trigger the onset of AD in the elderly. So far, studies have shown that SORLA can limit the amount of neurotoxic Abeta generated in the brain. However, since high levels of Abeta also are seen in aged individuals without symptoms of dementia or cognitive decline, neuroprotective mechanisms are likely in place to protect neurons from Abeta damage. We describe here that SORLA can limit the activation of a cell surface component EphA4 that is activated in the presence of Abeta, and which can damage synaptic function in the brain. Our preliminary results indicate that SORLA overexpression can limit Abeta-dependent activation of EphA4 in response to normal EphA4 activators such as Ephrin ligands, and Abeta in cultured neurons. Our pilot experiments indicate that mouse models overexpressing SORLA are less prone to Abeta injected into the mouse hippocampus. Our study here will confirm whether SORLA can limit toxic signals from EphA4 in response to Abeta, and whether molecular strategies to enhance SORLA/EphA4 interactions can further protect neurons from synaptic damage from Abeta. Together, this study may provide insight into a new pathway to protect neurons from Abeta damage, which may lead to strategies to improve cognition in AD patients.