The initial report on APOE as a susceptibility gene for late-onset Alzheimer's disease was presented a little more than two years ago. During the past year, several significant events have given added impetus to research into Alzheimer's. The association of increased allele frequency of APOE4 with Alzheimer's disease has been reproduced in several dozen laboratories around the world. The protective effect of the APOE2 allele has been reported and also rapidly verified. No evidence exists to support the notion of linkage disequilibrium with any nearby locus on chromosome 19. The neuropathological demonstration of apolipoprotein E (apoE) within neuronal cytoplasm in a location suitable for proposed interaction with microtubule-associated protein tau and MAP2c has introduced a new view of neuronal neurobiology. As apoE is not known to be expressed in neurons, its relationship with cellular receptors, such as the low-density lipoprotein related receptor, and the mechanism of intracellular trafficking are now important research problems. The role of apoE as a metabolic co-factor in neuronal metabolism presents new possibilities for neuronal mechanisms of maintenance and response to stress.