Identifying clinically useful biomarkers in neurodegenerative disease through a collaborative approach: the NeuroToolKit

Abstract

Abstract Background Alzheimer’s disease (AD) is a complex and heterogeneous disease, which requires reliable biomarkers for diagnosis and monitoring disease activity. Preanalytical protocol and technical variability associated with biomarker immunoassays makes comparability of biomarker data across multiple cohorts difficult. This study aimed to compare cerebrospinal fluid (CSF) biomarker results across independent cohorts, including participants spanning the AD continuum. Methods Measured on the NeuroToolKit (NTK) prototype panel of immunoassays, 12 CSF biomarkers were evaluated from three cohorts (ALFA+, Wisconsin, and Abby/Blaze). A correction factor was applied to biomarkers found to be affected by preanalytical procedures (amyloid-β1–42, amyloid-β1–40, and alpha-synuclein), and results between cohorts for each disease stage were compared. The relationship between CSF biomarker concentration and cognitive scores was evaluated. Results Biomarker distributions were comparable across cohorts following correction. Correlations of biomarker values were consistent across cohorts, regardless of disease stage. Disease stage differentiation was highest for neurofilament light (NfL), phosphorylated tau, and total tau, regardless of the cohort. Correlation between biomarker concentration and cognitive scores was comparable across cohorts, and strongest for NfL, chitinase-3-like protein-1 (YKL40), and glial fibrillary acidic protein. Discussion The precision of the NTK enables merging of biomarker datasets, after correction for preanalytical confounders. Assessment of multiple cohorts is crucial to increase power in future studies into AD pathogenesis.

Keywords

• Alzheimer’s disease
• Amyloid-β
• Cerebrospinal fluid biomarkers
• Glial activation
• Inflammation
• Neurodegeneration