CSF biomarker variability in the Alzheimer's Association quality control program
Authors: Mattsson Niklas , Andreasson Ulf , Persson Staffan , Carrillo Maria C. , Collins Steven , Chalbot Sonia , Cutler Neal , Dufour‐Rainfray Diane , Fagan Anne M. , Heegaard Niels H.H. , Robin Hsiung Ging‐Yuek , Hyman Bradley , Iqbal Khalid , Lachno D. Richard , Lleó Alberto , Lewczuk Piotr , Molinuevo José L. , Parchi Piero , Regeniter Axel , Rissman Robert , Rosenmann Hanna , Sancesario Giuseppe , Schröder Johannes , Shaw Leslie M. , Teunissen Charlotte E. , Trojanowski John Q. , Vanderstichele Hugo , Vandijck Manu , Verbeek Marcel M. , Zetterberg Henrik , Blennow Kaj , Käser Stephan A. ,   Alzheimer's Association QC Program Work Group, Rojo Aladro José A. , Albert Marilyn , Alcolea Daniel , Andreasson Ulf , Antonell Anna , Arai Hiroyuki , Archetti Silvana , Arkblad Eva , Baldeiras Inês , Bartos Ales , Batish Dev , Bedel Aurélie , Bentue‐Ferrer Daniele , Berisha Flora , Bernardini Sergio , Blankenstein Marinus , Blennow Kaj , Bousiges Olivier , Camuso Michael C. , Carrillo Maria , Casoli Tiziana , Cavallaro Sebastiano , Chalbot Sonia , Collins Steven , Cruz e Silva Odete , Cutler Neal , Cuvelier Isabelle , Delaroche Odile , Dufour‐Rainfray Diane , Dyer Roy , Engelborghs Sebastiaan , Fagan Anne M. , Fogli Anne , Forlenza Orestes V. , Fox Nick , Frisoni Giovanni , Galimberti Daniela , Galloni Elisabetta , Gritti Silvana , Gylys Karen H. , Hampel Harald , Haustein Sabine , Heath Theresa , Heegaard Niels H.H. , Heneka Michael T. , Herukka Sanna‐Kaisa , Holtzman David , Hsiung Ging‐Yuek Robin , Humpel Christian , Hyman Bradley , Iwatsubo Takeshi , Iqbal Khalid , Jardel Claude , Jucker Mathias , Kapaki Elisabeth , Käser Stephan A. , Kidd Daniel , Klivenyi Peter , Kuwano Ryozo , Lachno D. Richard , Lamari Foudil , Laplanche Jean‐Louis , Laser Jordan , Lehmann Sylvian , Lewczuk Piotr , Li Qiao‐Xin , Lleó Alberto , Maetzler Walter , Malaplate‐Armand Catherine , Martin Ralph , Martone Robert L. , Masters Colin , Mattsson Niklas , Mercken Marc , Molinuevo José Luis , Montine Tom , Nowatzke William , Otto Markus , Parchi Piero , Parent Xavier , Parnetti Lucilla , Persson Staffan , Petersen Ronald , Poesen Koen , Quadrio Isabelle , Quillard Muriel , Regeniter Axel , Rello Vara Luis , Rissman Robert , Rohan Zdenek , Rosenmann Hanna , Sancesario Giuseppe , Schröder Johannes , Shaw Leslie M. , Sisowath Christin , Skinningsrud Anders , Soares Holly , Soininen Hilkka , Søndersø Knudsen Cindy , Spreer Annette , Suardi Silvia , Teunissen Charlotte , Trojanowski John Q. , Umek Robert , Van Broeck Bianca , Vandenberghe Rik , Vanderstichele Hugo , Vandijck Manu , Vecsei Laszlo , Verbeek Marcel , Vostiar Igor , Windisch Manfred , Zetterberg Henrik 
Published: May 2013

Background

The cerebrospinal fluid (CSF) biomarkers amyloid beta 1–42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories.

Methods

Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single‐analyte enzyme‐linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection.

Results

A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within‐run CVs, less than 5% to 10%; and longitudinal within‐laboratory CVs, 5% to 19%. Interestingly, longitudinal within‐laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1–42 measurements, but for total tau and phosphorylated tau, between‐kit lot effects were much less than between‐laboratory effects. Despite the measurement variability, the between‐laboratory consistency in classification of samples (using prehoc‐derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP).

Conclusions

The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.