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 β-amyloid (A(3) oligomers (oAβ) vs monomeric Aβ in plasma and brain tissue of patients with sporadic and familial Alzheimer disease (AD) using a new enzyme-linked immunosor-bent assay (ELISA) specific for oAβ. Design: To establish the oAβ ELISA, the same N-terminal Aβ 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 Aβand new oAβ ELISAs. Subjects: We measured oAβ 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 Aβ and 4 mo-nomeric Aβ species in plasma samples from patients with AD and control subjects were measured by ELISA. Results: The specificity of the oAβ ELISA was validated with a disulfide-crossed-linked, synthetic Aβ _1-40Ser26Cys dimer that was specifically detected before but not after the dissociation of the dimers in β-mercaptoethanol. Plasma assays showed that relative oAβ levels were closely associated with relative Aβ 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 oAβand Aβ ₄₂ monomer levels over a 1-to 2-year period. In brain tissue from 9 patients with AD and 7 control subjects, both oAβand monomeric Aβ ₄₂ levels were consistently higher in the AD cases. Conclusions: An oAβ-specific ELISA reveals a tight link between oAβ and Aβ ₄₂ monomer levels in plasma and brain. Both forms can decline over time in plasma, presumably reflecting their increasing insolubility in the brain.