Amyloid-Beta Oligomerization in Alzheimer Dementia versus High-Pathology Controls

Objective: Although amyloid-beta (A beta) peptide deposition into insoluble plaques is a pathological hallmark of Alzheimer disease; soluble oligomeric A beta has been hypothesized to more directly underlie impaired learning and memory in dementia of the Alzheimer type. However, the lack of a sensitive, specific, and quantitative assay for A beta oligomers has hampered rigorous tests of this hypothesis. Methods: We developed a plate-based single molecule counting fluorescence immunoassay for oligomeric A beta sensitive to low pg/ml concentrations of synthetic A beta dimers using the same A beta-specific monoclonal antibody to both capture and detect A beta. The A beta oligomer assay does not recognize monomeric A beta, amyloid precursor protein, or other non-A beta peptide oligomers. Results: A beta oligomers were detected in aqueous cortical lysates from patients with dementia of the Alzheimer type and nondemented patients with A beta plaque pathology. However, A beta oligomer concentrations in demented patients' lysates were tightly correlated with A beta plaque coverage (r = 0.88), but this relationship was weaker in those from nondemented patients (r = 0.30) despite equivalent A beta plaque pathology. The ratio of A beta oligomer levels to plaque density fully distinguished demented from nondemented patients, with no overlap between groups in this derived variA beta le. Other A beta and plaque measures did not distinguish demented from nondemented patients. A beta oligomers were not detected in cerebrospinal fluid with this assay. Interpretation: The results raise the intriguing hypothesis that the linkage between plaques and oligomers may be a key pathophysiological event underlying dementia of the Alzheimer type. This A beta oligomer assay may be useful for many tests of the oligomer hypothesis. ANN NEUROL 2013;73:104-119