The amyloid hypothesis causatively relates the fibrillar deposits of amyloid beta peptide (A beta) to Alzheimer's disease (AD). More recent data, however, identify the soluble oligomers as the major cytotoxic entities. Pyroglutamylated A beta (pE-A beta) is present in AD brains and exerts augmented neurotoxicity, which is believed to result from its higher beta-sheet propensity and faster fibrillization. While this concept is based on a set of experimental results, others have reported similar beta-sheet contents in unmodified and pyroglutamylated A beta, and slower aggregation of pE-A beta as compared to unmodified A beta leaving the issue unresolved. Here, we assess the structural differences between A beta and pE-A beta peptides that may underlie their distinct cytotoxicities. Transmission electron microscopy identifies a larger number of prefibrillar aggregates of pE-A beta at early stages of aggregation and suggests that pE-A beta affects the fibrillogenesis even at low molar fractions. 'Circular dichroism and FTIR data indicate that while the unmodified A beta readily forms beta-sheet fibrils in aqueous media, pE-A beta displays increased alpha-helical and decreased beta-sheet propensity. Moreover, isotope-edited FTIR spectroscopy shows that pE-A beta reverses beta-sheet formation and hence fibrillogenesis of the unmodified A beta peptide via a prion-like mechanism. These data provide a novel structural mechanism for pE-A beta hypertoxicity; pE-A beta undergoes faster formation of prefibrillar aggregates due to its increased hydrophobicity, thus shifting the initial stages of fibrillogenesis toward smaller, hypertoxic oligomers of partial alpha-helical structure.