A Specific Enzyme-Linked Immunosorbent Assay for Measuring β-Amyloid Protein Oligomers in Human Plasma and Brain Tissue of Patients With Alzheimer Disease

Objective: To examine in vivo levels of beta-amyloid (A beta) oligomers (oA beta) vs monomeric A beta in plasma and brain tissue of patients with sporadic and familial Alzheimer disease (AD) using a new enzyme-linked immunosorbent assay (ELISA) specific for oA beta. Design: To establish the oA beta ELISA, the same N-terminal A beta antibody was used for antigen capture and detection. Plasma and postmortem brain tissue from patients with AD and control subjects were systematically analyzed by conventional monomeric A beta and new oA beta ELISAs. Subjects: We measured oA beta species in plasma samples from 36 patients with clinically well-characterized AD and 10 control subjects. In addition, postmortem samples were obtained from brain autopsies of 9 patients with verified AD and 7 control subjects. Main Outcome Measures: Oligomeric A beta and 4 monomeric A beta species in plasma samples from patients with AD and control subjects were measured by ELISA. Results: The specificity of the oA beta ELISA was validated with a disulfide-crossed- linked, synthetic A beta(1-40)Ser26Cys dimer that was specifically detected before but not after the dissociation of the dimers in beta-mercaptoethanol. Plasma assays showed that relative oA beta levels were closely associated with relative A beta(42) monomer levels across all of the subjects. Analysis of sequential plasma samples from a subset of the patients with AD, including a patient with AD caused by a presenilin mutation, revealed decreases in both oA beta and A beta(42) monomer levels over a 1- to 2-year period. In brain tissue from 9 patients with AD and 7 control subjects, both oA beta and monomeric A beta(42) levels were consistently higher in the AD cases. Conclusions: An oA beta-specific ELISA reveals a tight link between oA beta and A beta(42) monomer levels in plasma and brain. Both forms can decline over time in plasma, presumably reflecting their increasing insolubility in the brain.