Comparison of analytical platforms for cerebrospinal fluid measures of β-amyloid 1-42, total tau, and p-tau181 for identifying Alzheimer disease amyloid plaque pathology

Abstract

Background: Cerebrospinal fluid (CSF) biomarkers of Alzheimer disease (AD) are currently being considered for inclusion in revised diagnostic criteria for research and/or clinical purposes to increase the certainty of antemortem diagnosis.

Objective: To test whether CSF biomarker assays differ in their ability to identify true markers of underlying AD pathology (eg, amyloid plaques and/or neurofibrillary tangles) in living individuals.

Design: We compared the performances of the 2 most commonly used platforms, INNOTEST enzyme-linked immunosorbent assay and INNO-BIA AlzBio3, for measurement of CSF β-amyloid (Aβ) and tau proteins to identify the presence of amyloid plaques in a research cohort (n=103). Values obtained for CSF Aβ1-42, total tau, and phosphorylated tau 181 (p-tau(181)) using the 2 assay platforms were compared with brain amyloid load as assessed by positron emission tomography using the amyloid imaging agent Pittsburgh compound B.

Setting: The Knight Alzheimer's Disease Research Center at Washington University in St Louis, Missouri.

Subjects: Research volunteers who were cognitively normal or had mild to moderate AD dementia.

Results: The 2 assay platforms yielded different (approximately 2- to 6-fold) absolute values for the various analytes, but relative values were highly correlated. The CSF Aβ1-42 correlated inversely and tau and p-tau(181) correlated positively with the amount of cortical Pittsburgh compound B binding, albeit to differing degrees. Both assays yielded similar patterns of CSF biomarker correlations with amyloid load. The ratios of total tau to Aβ1-42 and p-tau(181) to Aβ1-42 outperformed any single analyte, including Aβ1-42, in discriminating individuals with vs without cortical amyloid.

Conclusions: The INNOTEST and INNO-BIA CSF platforms perform equally well in identifying individuals with underlying amyloid plaque pathology. Differences in absolute values, however, point to the need for assay-specific diagnostic cutoff values.

Figure 1

Relationship between the assay platforms for the various CSF analytes. Analytes include A) Aβ_1-42; B) total tau; C) P-tau₁₈₁; D) total tau/Aβ_1-42; and E) p-tau₁₈₁/Aβ_1-42. r, Spearman rho correlation coefficient.

Figure 2

Relationship between CSF analytes and cortical amyloid load. Analytes include A, B) Aβ_1-42; C, D) total tau; E, F) P-tau₁₈₁; G, H) total tau/Aβ_1-42; and I, J) p-tau₁₈₁/Aβ_1-42. Left panels, INNOTEST^®. Right panels, INNO-BIA. r, Spearman rho correlation coefficient.

Figure 3

Receiver operating characteristic (ROC) curves and area under the curve (AUC) describing CSF biomarker sensitivity and specificity for discriminating amyloid-positive (MCBP≥0.18) from amyloid-negative (MCBP<0.18) participants. CSF values were obtained with A) the INNOTEST^® or B) the INNO-BIA assay.