To explore whether the genetic linkage between apolipoprotein E (ApoE) alleles and susceptibility to Alzheimer's disease might be attributable to a direct molecular interaction between ApoE and the amyloid peptide A beta, we have produced ApoE variants in Escherichia coli and studied their interactions with A beta under native conditions. When incubated with A beta at 20-40 microM concentrations, all three isoforms of ApoE (2, 3, and 4) readily form complexes with A beta which can be isolated by gel filtration in native buffer. Freshly mixed ApoE and A beta generate a complex that co-migrates in gel filtration with the main A280 peak, which migrates identically to the ApoE tetramer alone. After several hours incubation, an additional, high molecular weight, soluble aggregate appears which also contains both ApoE and A beta. Neither ApoE nor A beta incubated by themselves produces high molecular weight aggregates under these conditions. Incubation of A beta with control proteins bovine serum albumin and immunoglobulin generates negligable binding in the gel filtration assay. Similar results were obtained whether A beta (1-40) or A beta (1-42) was used, and plasma-derived ApoE gave similar results to E. coli-produced material. The data are consistent with a role for ApoE-A beta interactions in modulating the development of AD. Since no major differences were observed in the behavior of the three ApoE isotypes, however, the molecular basis of the genetic trend between ApoE alleles and AD cannot be attributed to specific activity differences between the molecular forms of ApoE characterized in this study.