Large, poorly soluble aggregates of the amyloid-beta peptide form the senile plaques that are a pathological hallmark of Alzheimer’s disease, but the extent of plaque deposition correlates only moderately with dementia; for example many middle aged and elderly people have extensive plaque deposition without any signs of dementia. Instead, several types of smaller water soluble amyloid-beta oligomers have been found to be more toxic than either plaques or amyloid-beta peptide monomers. Our collaborative group has recently developed a sensitive, specific, quantitative and high-throughput assay for amyloid-beta oligomers. We propose to use this assay to facilitate purification of amyloid-beta oligomers from human brain tissue. We expect that there will be substantial complexity in the Alzheimer’s disease brain, with multiple oligomeric species having varying structural properties and toxicities. Once purified, we will use mass spectrometry to characterize the structure and cell-based toxicity assays to quantitatively assess the function of each distinct type of oligomer. The first major outcome will be identification of critical post-translational modifications, associated proteins, and conformational epitopes in amyloid-beta oligomers that could be targeted by innovative therapeutics. The second major outcome will be determining which (if any) animal models accurately reproduce the amyloid-beta oligomers found in the human brain so that candidate therapeutics targeting these oligomers can be tested appropriately in vivo. It may be that entirely new animal models will be needed. Thus, if successful, this project will facilitate an entirely new wave of preclinical and clinical therapeutic development for Alzheimer’s disease.