Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease - A comparative cerebrospinal fluid study

Background: Abnormal hyperphosphorylation of the micro tubule-associated protein tau and its incorporation into neurofibrillary tangles are major hallmarks of the pathogenesis of Alzheimer disease (AD). Different tau phosphoepitopes can be sensitively detected in cerebrospinal fluid (CSF). Objective: To compare the diagnostic accuracy of CSF concentrations of tau proteins phosphorylated at 3 pathophysiologically important epitopes (p-tau) to discriminate among patients with AD, nondemented control subjects, and patients with other dementias. Design and Setting: Cross-sectional, bicenter, memory clinic-based studies. Participants: One hundred sixty-one patients with a clinical diagnosis of AD, frontotemporal dementia, dementia with Lewy bodies, or vascular dementia and 45 nondemented controls (N = 206). Main Outcome Measures: Levels of tau protein phosphorylated at threonine 231 (p-tau(231)), threonine 181 (p-tau(181)), and serine 199 (p-tau(199)). The CSF p-tau protein levels were measured using 3 different enzyme-linked immunosorbent assays. Results: The mean CSF levels of the studied p-tau proteins were significantly elevated in patients with AD compared with the other groups. Applied as single markers, p-tau(231) and p-tau(181) reached specificity levels greater than 75% between AD and the combined non-AD group when sensitivity was set at 85% or greater. Statistical differences between the assay performances are presented. Particularly, discrimination between AD and dementia with Lewy bodies was maximized using p-tau(181) at a sensitivity of 94% and a specificity of 64%, and p-tau(231) maximized group separation between AD and frontotemporal dementia with a sensitivity of 88% and a specificity of 92%. Combinations of the 3 markers did not add discriminative power compared with the application as single markers. Conclusions: The p-tau proteins in CSF come closest to fulfilling the criteria of a biological marker of AD. There is a tendency for p-tau proteins to perform differently in the discrimination of primary dementia disorders from AD.