Amino-Truncated β-Amyloid42 Peptides in Cerebrospinal Fluid and Prediction of Progression of Mild Cognitive Impairment

Abstract

Abstract Background: Early identification of patients with mild cognitive impairment (MCI) progressing to Alzheimer disease (MCI-AD) by use of biomarkers in cerebrospinal fluid (CSF) is an essential step toward improving clinical diagnosis and drug development. We evaluated whether different β-amyloid42 (Aβ42) peptides can add further information to the combined use of tau and Aβ1–42 for predicting risk of progression of MCI to AD. Methods: We used xMAP® technology to simultaneously quantify different Aβ42 peptides modified at the amino terminus, tau, and phosphorylated tau (P-tau181P) in CSF. Aβ42 peptide concentrations were measured by use of immunoreactivity toward Aβ monoclonal antibodies [3D6 (Aβ42-3D6), WO2 (Aβ42-WO2), 6E10 (Aβ42-6E10), and 4G8 (Aβ42-4G8)]. The discriminant ability of the markers was evaluated by ROC curve analysis. Results: The areas under the curves for the separation of MCI-AD from nonprogressing MCI (MCI-N) were significantly higher when we used Aβ42-3D6/Aβ42-WO2, Aβ42-3D6/Aβ42-6E10, or Aβ42-3D6/Aβ42-4G8 compared with Aβ42-3D6. In addition, differentiation of MCI-N from MCI-AD was improved by quantification of full-length Aβ1–42 (Aβ42-3D6) compared with Aβ42-WO2, Aβ42-6E10, or Aβ42-4G8. Several Aβ42 peptides truncated at the amino terminus (Aβ11–42 and Aβ8–42) were identified in CSF by surface-enhanced laser desorption/ionization time-of-flight technology. Conclusion: The CSF markers tau, Aβ42 forms, and P-tau181P, when used as adjuncts to clinical diagnosis, have the potential to help identify AD pathology and could be a valuable asset for early AD diagnosis.