The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers

Abstract

Background: The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.

Methods: The program is open for laboratories using commercially available kits for Aβ, T-tau, or P-tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Mölndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples.

Results: Forty laboratories participated. Twenty-six used INNOTEST enzyme-linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO-BIA AlzBio3 kit (both measure Aβ-(1-42), P-tau(181P), and T-tau), and 5 used Meso Scale Discovery with the Aβ triplex (AβN-42, AβN-40, and AβN-38) or T-tau kits. The total coefficients of variation between the laboratories were 13% to 36%. Five laboratories analyzed the samples six times on different occasions. Within-laboratory precisions differed considerably between biomarkers within individual laboratories.

Conclusions: Measurements of CSF AD biomarkers show large between-laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers.

Fig. 1

Results for enzyme-linked immunosorbent assay (ELISA; A–C), xMAP (D–F), and Meso Scale Discovery (G–I) from rounds 1 (1A and 1B) and 2 (2A and 2B). Panels B, C, E, and F have secondary y-axes owing to large differences between samples. Different symbols indicate different kit batches for ELISA and xMAP, and different assays for Meso Scale Discovery (6E10, blue triangle; 4G8, red square).

Fig. 2

ELISA results from the reference laboratories from the first round. Results for sample 2009-1A are shown in panels A–C, and results for sample 2009-1B are shown in panels D–F.

Fig. 3

xMAP results from the reference laboratories from the first round. Results for sample 2009-1A are shown in panels A–C, and results for sample 2009-1B are shown in panels D–F. Data points missing in panels B and E are because of experimental error related to high background in the tau assay.

Fig. 4

ELISA results from the reference laboratories from the second round. Results for sample 2010-2A are shown in panels A–C, and results for sample 2010-2B are shown in panels D–F.

Fig. 5

xMAP results from the reference laboratories from the second round. Results for sample 2010-2A are shown in panels A–C, and results for sample 2010-2B are shown in panels D–F.