Apolipoprotein (apo) E is associated with the two characteristic neuropathologic lesions of Alzheimer's disease–extracellular neuritic plaques representing deposits of amyloid beta (Aβ) peptide and intracellular neurofibrillary tangles representing filaments of a microtubule-associated protein called tau. Incubation of the apoE4 isoform with the Aβ peptide in vitro results in the formation of a dense, stable network of very long monofibrils, while incubation of apoE3 with the Aβ peptide results in the formation of a less dense, less stable network. The more complex nature of the plaques formed with the Aβ peptide in the presence of apoE4 in vivo may impair the normal clearance process and enhance plaque formation. Alternatively or additionally, apoE may alter the cytoskeletal structure and function and, under certain conditions, may promote the formation of the neurofibrillary tangles. Our studies have demonstrated that apoE3 and apoE4 exert differential effects on neuronal growth (i.e., neurite extension and branching) in vitro. When combined with a source of lipid, apoE3 stimulated neurite extension in peripheral nervous system neurons (dorsal root ganglia), whereas apoE4 inhibited it. Similar results were obtained with central nervous system neurons (murine neuroblastoma Neuro-2a cells). Addition of free apoE3 or apoE4 without β-VLDL had no effect on neurite outgrowth. There was also differential accumulation of apoE3 and apoE4 by the neuroblastoma cells: apoE3 accumulated within cell bodies and neurites to a greater extent than apoE4. Thus, apoE3 may facilitate cytoskeletal activity, whereas apoE4 may inhibit it, which would be detrimental during synaptic remodeling.