Amyloid β-peptide (Aβ)1−42 oligomers have recently been discussed as intermediate toxic species in Alzheimer's disease (AD) pathology. Here we describe a new and highly stable Aβ1−42 oligomer species which can easily be prepared in vitro and is present in the brains of patients with AD and Aβ1−42-overproducing transgenic mice. Physicochemical characterization reveals a pure, highly water-soluble globular 60-kDa oligomer which we named ‘Aβ1−42 globulomer’. Our data indicate that Aβ1−42 globulomer is a persistent structural entity formed independently of the fibrillar aggregation pathway. It is a potent antigen in mice and rabbits eliciting generation of Aβ1−42 globulomer-specific antibodies that do not cross-react with amyloid precursor protein, Aβ1−40 and Aβ1−42 monomers and Aβ fibrils. Aβ1−42 globulomer binds specifically to dendritic processes of neurons but not glia in hippocampal cell cultures and completely blocks long-term potentiation in rat hippocampal slices. Our data suggest that Aβ1−42 globulomer represents a basic pathogenic structural principle also present to a minor extent in previously described oligomer preparations and that its formation is an early pathological event in AD. Selective neutralization of the Aβ globulomer structure epitope is expected to have a high potential for treatment of AD.