Apolipoprotein (apo-) E4 is associated with an increased risk of late-onset Alzheimer's disease. Apolipoprotein E4-enriched lipoproteins suppress neurite outgrowth from dorsal root ganglion neurons and neuroblastoma cellsin vitro. Free apo-E, which is not a ligand for lipoprotein receptors, does not affect neurite outgrowth. The inhibitory effect of apo-E-enriched lipoproteins on neurite outgrowth is mediated by the low density lipoprotein receptor-related protein and is associated with depolymerization of microtubules. The mechanism by which apo-E4 blocks neurite outgrowth (phenotypic differentiation) of these cells is unknown.