Brain plaque deposition in the form of amyloid-beta (Abeta) peptide is a pathological hallmark of Alzheimer's disease (AD). Apolipoprotein E (ApoE) is thought to be involved in plaque formation. Individuals afflicted with AD carrying the ApoE4 isoform have shown a greater number of Abeta plaques when compared to ApoE3 carriers, and inheritance of an ApoE4 allele increases the risk of AD when compared to ApoE2 and ApoE3 carriers. The role of ApoE in the pathogenesis of AD is not well understood but a hypothesis gaining widespread support is that ApoE is involved in deposition or clearance of Abeta by direct protein-to-protein interaction. We have established that various human Abeta conformations apparent during spontaneous aggregation confer differing degrees of binding to the three ApoE isoforms. When associated with lipid, ApoE4 bound preferentially to an intermediate aggregated form of Abeta and had higher avidity than did ApoE2 or ApoE3.