Recent evidence has established the colocalization of amyloid-rich plaques and heme-rich deposits in the human cerebral cortex as a common postmortem feature in Alzheimer's disease (AD). The amyloid beta (A beta) peptides have been shown to bind heme, and the resultant heme-A beta complexes can generate toxic partially reduced oxygen species (PROS) and exhibit peroxidase activity. The heme-A beta active site exhibits a concentration-dependent equilibrium between a high-spin mono-His-bound species similar to a peroxidase-type active site and a bis-His-bound six-coordinate low-spin species similar to that of a cytochrome b type active site. The nu(Fe-His) (241 cm(-1)) vibration has been identified in the high-spin heme-A beta active site by resonance Raman spectroscopy. The formation of the low-spin heme-A beta species is promoted by the His14 and non coordinating second-sphere ArgS residues. The high-spin state produces more PROS than the low-spin species. Nonbiological constructs modeling different forms of A beta (oligomers, fibrils, etc.) suggest that the detrimental high-spin state is likely to dominate under most physiological conditions.