a b s t r a c tIncreasing evidence indicates that beta-amyloid (Ab) oligomers rather than monomers or fibrils are the major toxic agents that specifically inhibit synaptic plasticity and long-term potentiation (LTP) in Alzheimer's disease (AD). Neutralization of Ab oligomeric toxicity was found to reverse memory deficits. Here, we report four single-chain variable fragment (scFv) antibodies isolated from the naive human scFv library by phage display that specifically recognized Ab oligomers but not monomers and fibrils. These conformation-dependent scFv antibodies inhibit both Ab fibrillation and cytotoxicity and bind to the same type of eptitope displayed on the Ab oligomers. Such scFv antibodies specifically targeting toxic Ab oligomers may have potential therapeutic and diagnostic applications for AD.