Multiple sclerosis (MS) is characterized by auto-reactive T cells that respond to central nervous system (CNS) based antigens and effect motor, sensory as well as behavioral and cognitive function.Cognitive deficits are considered debilitating and have a heavy impact economically and socially on the multiple sclerosis population.We and others have demonstrated a significant association between apolipoprotein E4 (APOE 4) and cognitive deficits in patients with MS.These results suggest a detrimental effect of the APOE 4 allele on cognition, particularly verbal learning and memory, in MS.The development of transgenic mouse models of APOE provides a template to investigate the early effects of APOE polymorphism on cognition in EAE, an animal model of MS.We applied a gene targeting approach to study the early effects ofAPOE 4 on cognition in EAE.We demonstrate the presence of deficits in learning and memory using the Morris water maze in the APOE transgenic mice after EAE induction.Further study localizes these deficits to the cholinergic system of the hippocampus.