New Assay for Old Markers-Plasma Beta Amyloid of Mild Cognitive Impairment and Alzheimer’s Disease

M.J. Chiu, S.Y. Yang, T.F. Chen, J.J. Chieh, T.Z. Huang, P.K. Yip, H.C. Yang, T.W. Cheng, Y.F. Chen, M.S. Hua, H.E. Horng

Abstract

Although there is a consensus on the reduced levels of Aβ1-42 in the CSF of patients with AD, studies of plasma Aβ levels were inconsistent and have limited clinical value. We developed an immunomagnetic reduction assay (IMR) to determine the plasma levels of Aβ. We surveyed patients with varying AD severity (CDR = 0.5, n=16; CDR ≥ 1, n=18) and controls (n=26). Significant group differences were apparent in the levels of Aβ1-42 (F = 5.54, p = 0.002) and the Aβ1-42/Aβ1-40 ratio (F = 24.198, p < 0.001). Post-hoc analyses showed significant differences in the Aβ1-42 levels of controls and AD patients (p = 0.001) and in the Aβ1-42/Aβ1-40 ratio of control, MCI and AD subjects (all p ≤ 0.001). Regression analysis of Aβ1-42/Aβ1-40 ratios on dementia severity showed an adjusted R2 of 0.553 (p = 0.001). We identified a cut-off of 16.1 pg/ml for Aβ1-42 to differentiate control subjects from patients (both AD and MCI) with 85.3% sensitivity and 88.5% specificity. We also obtained a cut-off value of 0.303 for Aβ1-42/Aβ1-40 ratios with 85.3% sensitivity and 96.2% specificity. APOE ε4 carriers had significantly higher Aβ1-42/Aβ1-40 ratios than the non-carriers (F = 4.839, p = 0.015). An independent group of case-control subjects validated both cut-off values for Aβ1-42/Aβ1-40 (100% sensitivity and 83.3% specificity) and for Aβ1-42 (100% sensitivity and 75.3% specificity). In a subgroup of longitudinal follow- up study, we found that the plasma Aβ was relatively stable with an interval of approximately 3 months. In conclusion, we found that the plasma Aβ1-42 is a useful biomarker for AD. The Aβ1-42/Aβ1-40 ratio improves the diagnostic power of the plasma Aβ biomarkers. The iron nanoparticles and IMR provides a novel method to measure plasma Aβ and could serve as an important clinical tool for the diagnosis of neurodegenerative diseases.

Keywords: Plasma beta-amyloid, Alzheimer’s disease, mild cognitive impairment, immunomagnetic reduction assay, nanoparticles, neurofibrillary tangles, albumin, lipoproteins, carcinogens