Oligomeric forms of amyloid-β protein in plasma as a potential blood-based biomarker for Alzheimer's disease

Abstract

Background: Soluble amyloid-β (Aβ) oligomers are the major toxic substances associated with the pathology of Alzheimer's disease (AD). The ability to measure Aβ oligomer levels in the blood would provide simple and minimally invasive tools for AD diagnostics. In the present study, the recently developed Multimer Detection System (MDS) for AD, a new enzyme-linked immunosorbent assay for measuring Aβ oligomers selectively, was used to detect Aβ oligomers in the plasma of patients with AD and healthy control individuals.

Methods: Twenty-four patients with AD and 37 cognitively normal control individuals underwent extensive clinical evaluations as follows: blood sampling; detailed neuropsychological tests; brain magnetic resonance imaging; cerebrospinal fluid (CSF) measurement of Aβ42, phosphorylated tau protein (pTau), and total tau protein (tTau); and ¹¹C-Pittsburgh compound B (PIB) positron emission tomography. Pearson's correlation analyses between the estimations of Aβ oligomer levels by MDS and other conventional AD biomarkers (CSF Aβ₄₂, pTau, and tTau, as well as PIB standardized uptake value ratio [PIB SUVR]) were conducted. ROC analyses were used to compare the diagnostic performance of each biomarker.

Results: The plasma levels of Aβ oligomers by MDS were higher in patients with AD than in normal control individuals, and they correlated well with conventional AD biomarkers (levels of Aβ oligomers by MDS vs. CSF Aβ₄₂, r = -0.443; PIB SUVR, r = 0.430; CSF pTau, r = 0.530; CSF tTau, r = 0.604). The sensitivity and specificity of detecting plasma Aβ oligomers by MDS for differentiating AD from the normal controls were 78.3% and 86.5%, respectively. The AUC for plasma Aβ oligomers by MDS was 0.844, which was not significantly different from the AUC of other biomarkers (p = 0.250).

Conclusions: Plasma levels of Aβ oligomers could be assessed using MDS, which might be a simple, noninvasive, and accessible assay for evaluating brain amyloid deposition related to AD pathology.

Keywords: Alzheimer’s disease; Amyloid-β protein; Biomarker; Oligomer.

Fig. 1

The Multimer Detection System concept. a Monomers are proteins with a single epitope that can be captured by an antibody (capturing antibody 6E10) attached to the surface of the plate. After the addition of a detection antibody (FF51-horseradish peroxidase [HRP]), monomer proteins cannot be detected, because the single epitope is already occupied. b Multimers with numerous epitopes can be detected by detection antibodies. The capturing and detection antibodies are different, but their epitopes overlap. ELISA Enzyme-linked immunosorbent assay

Fig. 2

The distribution pattern of plasma amyloid-β oligomers determined using the Multimer Detection System (MDS) in patients with Alzheimer’s disease (AD) and cognitively normal control subjects (NC). The MDS relative luminescence units (RLUs) were higher in the AD group than in the NC group (p < 0.0001). The horizontal bar is the median MDS RLU. However, there was an overlap between the two groups, suggesting that further optimization of the MDS is required

Fig. 3

Correlations between plasma Aβ oligomer levels determined using the Multimer Detection System, and other amyloid biomarkers of Alzheimer’s disease. a There was a negative correlation between CSF Aβ₄₂ levels and the PIB SUVR. b Plasma Aβ oligomer levels were moderately negatively correlated with CSF Aβ₄₂ levels. c There was a positive correlation between plasma Aβ oligomer levels and PIB SUVR. d CSF pTau and e tTau levels also correlated positively with plasma Aβ oligomer levels. MDS RLU Multimer Detection System relative luminescence units, CSF Aβ ₄₂ Cerebrospinal fluid amyloid-β 1–42 peptide, PIB SUVR ¹¹C-Pittsburgh compound B standardized uptake value ratio, pTau Phosphorylated tau protein, tTau Total tau protein, AD Patients with Alzheimer’s disease, NC Cognitively normal control subjects

Fig. 4

ROC analysis of plasma Aβ oligomer levels measured using the MDS. a ROC analysis showed that plasma Aβ oligomer levels measured using MDS could discriminate between the AD and NC groups with an AUC of 0.844. The best sensitivity and specificity were 78.3% and 86.5%, respectively. b The AUCs for the biomarkers were as follows: PIB SUVR (AUC 0.9707, 95% CI 0.9309–1.000), CSF tTau/Aβ42 ratio (AUC 0.9689, 95% CI 0.9285–1.000), and CSF pTau/Aβ42 ratio (AUC 0.9542, 95% CI 0.8916–1.000). The AUC for plasma Aβ oligomer levels had the lowest value (AUC 0.8645, 95% CI 0.7535–0.9754) among those of other biomarkers of Alzheimer’s disease, although the difference was not statistically significant (p = 0.2503). Sn Sensitivity, Sp Specificity, MDS RLU Multimer Detection System relative luminescence units, PIB SUVR ¹¹C-Pittsburgh compound B standardized uptake value ratio, CSF Aβ ₄₂ Cerebrospinal fluid amyloid-β 1–42, CSF tTau/Aβ ₄₂ Cerebrospinal fluid total tau protein/Aβ₄₂ ratio, CSF pTau/Aβ ₄₂ Cerebrospinal fluid phosphorylated tau protein/Aβ₄₂ ratio