. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. 2020 Aug 25;324(8):772-781. PubMed.

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  1. The paper by Palmqvist et al. on blood plasma phospho-tau 217 is a remarkable clinical study clearly demonstrating the value of phospho-tau 217 for identifying AD pathology. These findings advance our understanding of how p-tau217 is related to amyloid and tau PET and the stages of AD, and how it can be utilized as a blood biomarker. By using cutoffs and AUC analyses, the group was able to demonstrate outstanding concordance of blood plasma p-tau217 to amyloid and tau PET thresholds.

    Based on findings in CSF from the DIAN study (Barthélemy et al., 2020), some outstanding questions remain related to the causal relationship of p-tau217 and other tau species with amyloid plaques and neurofibrillary tangles. For example, p-tau217 increases two decades before tau PET increases are detected in DIAN. Does this indicate that p-tau217 is a reaction to amyloid plaques that precedes tau pathology? Or is tau pathology beginning two decades before it’s detectable by tau PET? Similarly, p-tau217 decreases after symptom onset, while tau PET signal and clinical dementia is increasing. This evidence strongly suggests that p-tau217 (and p-tau181) are not direct measures of tau pathology, but rather may be a reaction to amyloid plaques that later is associated to tau pathology.

    Nico Barthélemy’s work identified p-tau217 as a promising biomarker, and that CSF p-tau217 performed better than p-tau181 to identify amyloid PET positivity (2016 CTAD presentation; Barthélemy et al., 2017; Barthélemy et al., 2020). These findings are supported by extensive brain mass-spectrometry analyses of multiple tau isoforms and species (Barthélemy et al., 2019). 

    Our latest work identifies that plasma p-tau by mass spectrometry continues to produce better associations with amyloid plaques, and that it is feasible to measure blood plasma p-tau181 and p-tau217 in a mass-spec multiplex assay. Further work will be needed to better understand, and interpret, changes in p-tau217 and other tau biomarkers in AD.

    References:

    . A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer's disease. Nat Med. 2020 Mar;26(3):398-407. Epub 2020 Mar 11 PubMed.

    . Tau hyperphosphorylation on T217 in cerebrospinal fluid is specifically associated to amyloid-β pathology. bioRxiv. November 30, 2017.

    . Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer's disease and PET amyloid-positive patient identification. Alzheimers Res Ther. 2020 Mar 17;12(1):26. PubMed.

    . Tau Phosphorylation Rates Measured by Mass Spectrometry Differ in the Intracellular Brain vs. Extracellular Cerebrospinal Fluid Compartments and Are Differentially Affected by Alzheimer's Disease. Front Aging Neurosci. 2019;11:121. Epub 2019 May 21 PubMed.

    View all comments by Randall Bateman

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  1. Plasma p-Tau217 Set to Transform Alzheimer’s Diagnostics