Extracellular plaques of amyloid-beta and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer's disease. Plaques comprise amyloid-beta fibrils that assemble from monomeric and oligomeric intermediates, and are prognostic indicators of Alzheimer's disease. Despite the importance of plaques to Alzheimer's disease, oligomers are considered to be the principal toxic forms of amyloid-beta(1,2). Interestingly, many adverse responses to amyloid-beta, such as cytotoxicity(3), microtubule loss(4), impaired memory and learning(5), and neuritic degeneration(6), are greatly amplified by tau expression. Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-beta(7,8) are strongly associated with Alzheimer's disease, are more toxic than amyloid-beta, residues 1-42 (A beta(1-42)) and A beta(1-40), and have been proposed as initiators of Alzheimer's disease pathogenesis(9,10). Here we report a mechanism by which pE-A beta may trigger Alzheimer's disease. A beta(3(pE)-42) co-oligomerizes with excess A beta(1-42) to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from A beta(1-42) alone. Tau is required for cytotoxicity, and LNOs comprising 5% A beta(3(pE)-42) plus 95% A beta(1-42) (5% pE-A beta) seed new cytotoxic LNOs through multiple serial dilutions into A beta(1-42) monomers in the absence of additional A beta(3(pE)-42). LNOs isolated from human Alzheimer's disease brain contained A beta(3(pE)-42), and enhanced A beta(3(pE)-42) formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. We conclude that A beta(3(pE)-42) confers tau-dependent neuronal death and causes template-induced misfolding of A beta(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that A beta(3(pE)-42) acts similarly at a primary step in Alzheimer's disease pathogenesis.