An emerging paradigm for degenerative diseases associated with protein misfolding, such as Alzheimer's disease, is the formation of a toxic species due to structural transitions accompanied by oligomerization. Increasingly, the focus in Alzheimer's disease is on soluble oligomeric forms of the amyloid-beta peptide (AB) as the potential toxic species. Using a variety of methods, we have analyzed how sodium dodecyl sulphate (SDS) modulates the folding of A beta 40 and 42 and found that submicellar concentrations of SDS solubilize A beta and induce structural transitions. Under these conditions, A beta 40 and 42 are interconverting oligomeric ensembles with a predominantly beta-sheet structure. The A beta 42 soluble oligomers form beta-sheet structures more readily and have increased stability compared with A beta 40 under identical conditions. The presence of added Cu2+ significantly promotes and stabilizes the formation of the soluble oligomeric beta-sheet structures but these structures are nonamyloidogenic. In contrast, in the absence of added Cu2+, these beta-sheet oligomers possess the hallmarks of amyloidogenic structures. These SDS-induced beta-sheet forms of A beta, both in the presence and absence of Cu2+, are toxic to neuronal cells.