beta-Amyloid protein (A beta) is the major component of senile plaques found in the brains of Alzheimer's patients. A novel ELISA has been developed which probes the early stages of oligomerization of A beta. Incubation of A beta solutions at 37 degrees C and pH 7.4 produces soluble oligomers in a concentration-dependent manner. Fresh A beta 42 solutions rapidly form soluble oligomers, whereas A beta 40 solutions require prolonged incubation to produce oligomers. Fresh A beta 42 solutions are more toxic to human neuroblastoma SH-SY5Y cells than A beta 40 solutions, possibly mediated by soluble oligomers. The differences between A beta 42 and A beta 40 could explain the association of the longer form with familial early-onset Alzheimer's disease. We also report a new strategy for solid-phase synthesis of A beta peptides which gives high yield and purity of the initial crude preparation.