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 ␤-amyloid (A␤) oligomers (oA␤) vs monomeric A␤ 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␤.Design: To establish the oA␤ ELISA, the same Nterminal A␤ 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␤ and new oA␤ ELISAs. Subjects:We measured oA␤ 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␤ and 4 monomeric A␤ species in plasma samples from patients with AD and control subjects were measured by ELISA. Results:The specificity of the oA␤ ELISA was validated with a disulfide-crossed-linked, synthetic A␤ 1-40 Ser26Cys dimer that was specifically detected before but not after the dissociation of the dimers in ␤-mercaptoethanol.Plasma assays showed that relative oA␤ levels were closely associated with relative A␤ 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␤ and A␤ 42 monomer levels over a 1-to 2-year period.In brain tissue from 9 patients with AD and 7 control subjects, both oA␤ and monomeric A␤ 42 levels were consistently higher in the AD cases.Conclusions: An oA␤-specific ELISA reveals a tight link between oA␤ and A␤ 42 monomer levels in plasma and brain.Both forms can decline over time in plasma, presumably reflecting their increasing insolubility in the brain.