Abstract
INTRODUCTION: Amyloid- and tau-positron emission tomography (PET) are promising modalities for detecting pathological changes associated with Alzheimer's disease (AD); however, their application is limited. Although the use of cerebrospinal fluid (CSF) biomarkers as alternatives to amyloid-PET and tau-PET has been explored, no in vitro diagnostic-approved or commercial CSF biomarker assays are currently available for detecting tau pathology in clinical practice. METHODS: In this study, we determined and validated the optimal cutoff value for the ratio of tau phosphorylated at a threonine residue at position 181 (pTau(181)) to β-amyloid(1-42) (Aβ(42)) in CSF, measured with the Elecsys(®) Phospho-Tau (181P) CSF and β-Amyloid(1-42) CSF immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland), based on its concordance with binary tau-PET status. Clinical performance was explored using CSF measurements and tau-PET scans retrospectively obtained from a subset of subjects with mild cognitive impairment and dementia due to AD in two independent cohorts, Alzheimer's Disease Neuroimaging Initiative-2/3 (ADNI-2/3; N = 133) and Swedish BioFINDER-2 (N = 62). RESULTS: In the first part of this analysis (ADNI-2/3 pre-analytics), a CSF pTau(181)/Aβ(42) cutoff value of 0.0395 was selected as the best compromise between positive percent agreement (PPA) and negative percent agreement (NPA) for the tau-PET visual read endpoint. After adjustment to account for differences between the ADNI-specific protocol and the manufacturer's recommended pre-analytical protocol used in BioFINDER-2, the optimal CSF pTau(181)/Aβ(42) cutoff value was set at 0.037. The adjusted cutoff was validated in BioFINDER-2 and was associated with a PPA of 85.7% (95% confidence interval [CI] 70.6, 93.7), NPA of 70.4% (95% CI 51.5, 84.1), and overall percent agreement (OPA) of 79.0% (95% CI 67.4, 87.3); the positive and negative likelihood ratios were 2.89 and 0.203, respectively. CONCLUSION: The Elecsys CSF pTau(181)/Aβ(42) ratio may be a reliable tool for identifying tau pathology in clinical practice.