In the United States in 2013, 5.2 million people are estimated to suffer from Alzheimer's disease, with as many as 50% being undiagnosed [Alzheimer's Association 2013]. Current diagnostic technologies for Alzheimer's disease are based on the levels of total soluble amyloid beta (Abeta) peptide in plasma and/or cerebrospinal fluid (CSF), levels of tau and phosphorylated tau protein in CSF, or the levels of insoluble amyloid plaques in the brain [e.g., Mulder 2010]. None of the current Alzheimer's disease diagnostic/biomarker technologies detect or quantitate soluble Abeta oligomers. Soluble Abeta oligomers, in contrast to monomeric Abeta or fibrillic Abeta (amyloid plaques), are primary synaptic toxins that cause acute, but reversible, cognitive deficits and the chronic neuronal degeneration of Alzheimer's disease [Walsh 2007, Roychaudhuri 2009, Benilova 2012]. Although the presence of soluble Abeta oligomers in postmortem extracts of human brain tissue is well documented, because non-toxic Abeta monomer and relatively non-toxic Abeta plaques are present in human Alzheimer's brain at levels that are orders of magnitude greater than soluble Abeta oligomers, it is challenging to develop diagnostic techniques that quantitate soluble Abeta oligomers. Detection and quantitation of soluble Abeta oligomers in living patients would provide a valuable tool as a diagnostic to identify very early stage Alzheimer's disease patients and for the development of therapies for Alzheimer's disease. Preliminary studies suggest that soluble Abeta oligomer selective antibodies coupled with Singulex- Erenna(R) technology is an ultra-high sensitivity detection assay for soluble Abeta-oligomers with a detection limit of 0.1-0.5 pg/mL and a 5000-fold selectivity for Abeta oligomers vs. monomer [Wolfe 2012]. Reliable measurements were achieved in CSF from Alzheimer's disease patients with average soluble Abeta oligomer levels of 2 pg/mL, compared to control patients with average levels of 0.6 pg/mL. Initial findings from a small number of samples showed an inverse correlation between cognitive abilities and CSF levels of soluble Abeta oligomers, suggesting a reliable and quantitative biomarker of Abeta-mediated Alzheimer's disease. The objective of this Phase I SBIR study is twofold: (1) to validate the selectivity and sensitivity of an Acumen proprietary soluble Abeta oligomer selective antibody in the Singulex-Erenna(R) assay for quantitating soluble Abeta oligomers in human CSF, and (2) demonstrate the potential commercial utility of the technology by quantitating levels of soluble Abeta oligomers in CSF samples from 50 Alzheimer's disease patients and 20 non-diseased control patients.
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