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:
Barthélemy NR, Li Y, Joseph-Mathurin N, Gordon BA, Hassenstab J, Benzinger TL, Buckles V, Fagan AM, Perrin RJ, Goate AM, Morris JC, Karch CM, Xiong C, Allegri R, Mendez PC, Berman SB, Ikeuchi T, Mori H, Shimada H, Shoji M, Suzuki K, Noble J, Farlow M, Chhatwal J, Graff-Radford NR, Salloway S, Schofield PR, Masters CL, Martins RN, O'Connor A, Fox NC, Levin J, Jucker M, Gabelle A, Lehmann S, Sato C, Bateman RJ, McDade E, Dominantly Inherited Alzheimer Network.
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.
Barthélemy NR, Bateman RJ, Marin P, Becher F, Sato C, Lehmann S, Gabelle A.
Tau hyperphosphorylation on T217 in cerebrospinal fluid is specifically associated to amyloid-β pathology.
bioRxiv. November 30, 2017.
Barthélemy NR, Bateman RJ, Hirtz C, Marin P, Becher F, Sato C, Gabelle A, Lehmann S.
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.
Barthélemy NR, Mallipeddi N, Moiseyev P, Sato C, Bateman RJ.
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.
Comments
Washington University School of Medicine
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:
Barthélemy NR, Li Y, Joseph-Mathurin N, Gordon BA, Hassenstab J, Benzinger TL, Buckles V, Fagan AM, Perrin RJ, Goate AM, Morris JC, Karch CM, Xiong C, Allegri R, Mendez PC, Berman SB, Ikeuchi T, Mori H, Shimada H, Shoji M, Suzuki K, Noble J, Farlow M, Chhatwal J, Graff-Radford NR, Salloway S, Schofield PR, Masters CL, Martins RN, O'Connor A, Fox NC, Levin J, Jucker M, Gabelle A, Lehmann S, Sato C, Bateman RJ, McDade E, Dominantly Inherited Alzheimer Network. 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.
Barthélemy NR, Bateman RJ, Marin P, Becher F, Sato C, Lehmann S, Gabelle A. Tau hyperphosphorylation on T217 in cerebrospinal fluid is specifically associated to amyloid-β pathology. bioRxiv. November 30, 2017.
Barthélemy NR, Bateman RJ, Hirtz C, Marin P, Becher F, Sato C, Gabelle A, Lehmann S. 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.
Barthélemy NR, Mallipeddi N, Moiseyev P, Sato C, Bateman RJ. 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.
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