Professor Klein’s team is helping lead the way toward a molecular basis for the cause, diagnosis, and treatment of Alzheimer’s disease. In an early breakthrough study, Prof. Klein’s team introduced the idea that neuron damage leading to AD is instigated by small toxic oligomers of the Aβ peptide. This new idea emerged from their discovery that oligomers are potent CNS toxins that rapidly destroy synaptic memory mechanisms. His ongoing research is highly collaborative and concerns five areas. (1) Therapeutics. AβOs are excellent targets because of their early role in causing brain damage. Therapeutic monoclonal antibodies are nearing clinical trials due to partnering between pharma and Acumen, a biotech built on our past work. New programs for drug discovery focus on insulin signaling (to block AβO toxicity) and on high throughput screening using nanoscale synaptic membrane mimetics (to obtain compounds that prevent AβO binding to toxin receptors). (2) Diagnostics. AβOs provide an optimal target for diagnostics because they appear early in disease and instigate the path to dementia. Ultrasensitive assays for clinical chemistry are being developed along with unique approaches to brain imaging by PET and molecular MRI. (3) Etiology. The cause of AβO build up in in late-onset AD is a major unknown. We are taking new approaches using non-transgenic models to investigate metabolic factors such as high sugar and fat diets associated with diabetes and hypercholesterolemia. (4) Cell and molecular mechanisms of memory loss. How neuron damage is triggered by AβOs is being investigated in brain cell culture systems and animal models. Experiments focus on early steps in the toxic mechanism. These include binding to toxin receptors, disrupted trafficking of ion channels and GPCRs, and altered signaling pathways. (5) Structural biology. State-of-the-art facilities are being used to discover the molecular organization of synthetic and brain-derived toxic oligomers. AβO structure is still poorly understood because of the difficulty in characterizing dynamic populations of oligomers in extremely dilute solutions. Approaches include cryoEM and unique native protein mass spectrometry.