Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer\u2019s disease

Shorena Janelidze,Gallen Triana-Baltzer,Oskar Hansson,John R Sims,Sebastian Palmqvist,Niklas Mattsson,Jeffrey L Dage,Nicholas K Proctor,Ruben Smith,Marc Mercken,Clara Theunis,Randy Slemmon,David C Airey,Xiyun Chai,Erik Stomrud,Hartmuth Kolb,Sergey Shcherbinin

doi:10.1038/s41467-020-15436-0

Abstract

Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n = 194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer [18F]flortaucipir, and more accurately identifies individuals with abnormally increased [18F]flortaucipir retention. Furthermore, longitudinal increases in p-tau217 are higher compared to p-tau181 and better correlate with [18F]flortaucipir uptake. P-tau217 correlates better than p-tau181 with CSF and PET measures of neocortical amyloid-β burden and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and [18F]flortaucipir are corroborated in an independent EXPEDITION3 trial cohort (n = 32). The main results are validated using a different p-tau217 immunoassay. These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.

Highlights

Cerebrospinal fluid (CSF) p-tau[181] is an established biomarker of Alzheimer’s disease (AD), reflecting abnormal tau metabolism in the brain
Tau positron emission tomography (PET) measures were moderate in AD dementia, but weak or absent in cognitively unimpaired individuals and mild cognitive impairment (MCI) patients[19,20,21]
These finding are not surprising given that CSF concentrations of p-tau mirror abnormal tau metabolism at a time of lumbar puncture whereas Tau PET is a measure of accumulation of insoluble paired helical filament tau over the disease course

Summary

Introduction

Cerebrospinal fluid (CSF) p-tau[181] (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD), reflecting abnormal tau metabolism in the brain. To assess whether increases in CSF p-tau levels in AD reflect hyperphosphorylation of specific residues in the brain or global changes in tau resulting from increased production and secretion, we compared p-tau[217] and p-tau[181] with t-tau, p-tau217/t-tau and p-tau181/t-tau Both p-tau isoforms were measured using ELISA kits including the same detection antibody which limited the effects of reagent variability and allowed accurate comparison of biomarker performance. We found that CSF p-tau[217] correlates stronger than p-tau[181] with PET measures of tau and amyloid pathologies in AD and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders These results suggest potential benefit of implementing CSF p-tau[217] as a biomarker of AD in clinical practice

Methods

Results

Conclusion