Cerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases

Linda Karlsson (), Jacob Vogel, Ida Arvidsson, Kalle Åström, Shorena Janelidze, Kaj Blennow, Sebastian Palmqvist, Erik Stomrud, Niklas Mattsson-Carlgren and Oskar Hansson ()
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Linda Karlsson: Lund University
Jacob Vogel: Lund University
Ida Arvidsson: Lund University
Kalle Åström: Lund University
Shorena Janelidze: Lund University
Kaj Blennow: University of Gothenburg
Sebastian Palmqvist: Lund University
Erik Stomrud: Lund University
Niklas Mattsson-Carlgren: Lund University
Oskar Hansson: Lund University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Cerebrospinal fluid (CSF) biomarkers reflect brain pathophysiology and are used extensively in translational research as well as in clinical practice for diagnosis of neurological diseases, e.g., Alzheimer’s disease (AD). However, CSF biomarker concentrations may be influenced by non-disease related inter-individual variability. Here we use a data-driven approach to demonstrate the existence of inter-individual variability in mean standardized CSF protein levels. We show that these non-disease related differences cause many commonly reported CSF biomarkers to be highly correlated, thereby producing misleading results if not accounted for. To adjust for this inter-individual variability, we identified and evaluated high-performing reference proteins which improved the diagnostic accuracy of key CSF AD biomarkers. Our reference protein method attenuates the risk for false positive findings, and improves the sensitivity and specificity of CSF biomarkers, with broad implications for both research and clinical practice.

Date: 2024
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DOI: 10.1038/s41467-024-47971-5

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