Recently, it has been shown that heme binds to A beta peptides which may play a major role in Alzheimer's disease (AD). This study illustrates that A beta peptides can bind both Cu and heme cofactors at the same time. Both cofactors have unique spectroscopic and electrochemical features which are unaffected in the presence of the other, implying that they are electronically, chemically, and electrochemically uncoupled. These data clearly indicate that Cu cannot bind to three histidine residues simultaneously in Cu-A beta complexes as previously proposed, since one of the histidines is involved in binding heme. The heme-A beta and the heme-Cu-A beta peptide complexes function as peroxidases. Interestingly, the Cu-A beta complex also exhibits peroxidase activity, which may have significant implications in AD. Both Cu+-A beta and heme (Fe2+)-A beta complexes reduce O-2 to H2O2 quantitatively. Only one of the two electrons that are required for the reduction of O-2 to H2O2 is derived from the reduced metal site, while the Tyr(10) residue of the native A beta peptide donates the second electron. This Tyr(10) residue, the source of electron for the generation of partially reduced oxygen species (PROS, e.g., H2O2) is absent in rodents, which do not get affected by AD. When both heme and Cu are bound to the A beta peptides, which is likely to happen physiologically, the amount of toxic PROS generated is maximum, implying that heme-Cu-A beta complexes could potentially be most toxic for AD.