CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer’s disease

Barthélemy, Nicolas R.; Saef, Benjamin; Li, Yan; Gordon, Brian A.; He, Yingxin; Horie, Kazuyuki; Stomrud, Erik; Salvadó, Gemma; Janelidze, Shorena; Sato, Chihiro; Ovod, Vitaliy; Henson, Rachel L.; Benzinger, Tammie L.S.; Xiong, Chengjie; Morris, John C.; Hansson, Oskar; Bateman, Randall J.; Schindler, Suzanne E.

doi:10.1038/s43587-023-00380-7

Cited by 47 publications

(62 citation statements)

References 51 publications

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“…This study evaluates a commercially available assay for p-tau217 that exhibits similar advantageous features to those previously reported. Consistent with Palmqvist et al, this assay outperformed magnetic resonance imaging and showed comparable performance with CSF biomarkers in detecting Aβ PET positivity and tau PET positivity . Further, significant superiority to other plasma p-tau epitopes, Aβ42/40, NfL, and GFAP and their optimal combinations was shown.…”

Section: Discussionsupporting

confidence: 80%

Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

Ashton,

Brum,

Di Molfetta

et al. 2024

JAMA Neurol

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ImportancePhosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests.ObjectiveTo determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid β (Aβ) and longitudinal change across 3 selected cohorts.Design, Setting, and ParticipantsThis cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017–August 2021) and Wisconsin Registry for Alzheimer’s Prevention (WRAP) cohort (visits February 2007–November 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009–November 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023.ExposuresMagnetic resonance imaging, Aβ positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (Aβ42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay).Main Outcomes and MeasuresAccuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status.ResultsThe study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated Aβ (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signal. The detection of abnormal Aβ pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in Aβ-positive individuals, with the highest increase observed in those with tau positivity.Conclusions and RelevanceThis study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage.

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Section: Discussionsupporting

confidence: 80%

Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

Ashton,

Brum,

Di Molfetta

et al. 2024

JAMA Neurol

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“…The current data show extensive pT217‐tau “trapping” endosomes, including endosomes associated with Aβ42, suggesting that pT217‐tau may be involved in the etiology of amyloid pathology. This hypothesis may help to explain why plasma pT217‐tau levels correlate so highly with amyloid pathology in humans 60,76 . Although it is widely considered that Aβ drives tau phosphorylation, the current data suggest that the converse may also be true and that the extensive aggregation of pT217‐tau on microtubules may help to explain the correlation with this particular phosphorylated tau species.…”

Section: Discussionmentioning

confidence: 61%

Nanoscale imaging of pT217‐tau in aged rhesus macaque entorhinal and dorsolateral prefrontal cortex: Evidence of interneuronal trafficking and early‐stage neurodegeneration

Datta,

Perone,

Wijegunawardana

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONTau phosphorylated at threonine‐217 (pT217‐tau) is a novel fluid‐based biomarker that predicts onset of Alzheimer's disease (AD) symptoms, but little is known about how pT217‐tau arises in the brain, as soluble pT217‐tau is dephosphorylated post mortem in humans.METHODSWe used multilabel immunofluorescence and immunoelectron microscopy to examine the subcellular localization of early‐stage pT217‐tau in entorhinal and prefrontal cortices of aged macaques with naturally occurring tau pathology and assayed pT217‐tau levels in plasma.RESULTSpT217‐tau was aggregated on microtubules within dendrites exhibiting early signs of degeneration, including autophagic vacuoles. It was also seen trafficking between excitatory neurons within synapses on spines, where it was exposed to the extracellular space, and thus accessible to cerebrospinal fluid (CSF)/blood. Plasma pT217‐tau levels increased across the age span and thus can serve as a biomarker in macaques.DISCUSSIONThese data help to explain why pT217‐tau predicts degeneration in AD and how it gains access to CSF and plasma to serve as a fluid biomarker.

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“…We found that the plasma levels of pTau-217 and NTA-tau showed the highest accuracy for separating A+T+ and A+T-. At the group level, pTau-217 is already elevated in the CSF 28 and blood in cognitively unimpaired individuals who have Aβ pathology. However, previous studies showed that pTau-217 correlates more strongly with Aβ brain load than tau accumulation measured by PET.…”

Section: Discussionmentioning

confidence: 96%

Plasma pTau‐217 and N‐terminal tau (NTA) enhance sensitivity to identify tau PET positivity in amyloid‐β positive individuals

Woo,

Tissot,

Lantero‐Rodriguez

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONWe set out to identify tau PET‐positive (A+T+) individuals among amyloid‐beta (Aβ) positive participants using plasma biomarkers.METHODSIn this cross‐sectional study we assessed 234 participants across the AD continuum who were evaluated by amyloid PET with [18F]AZD4694 and tau‐PET with [18F]MK6240 and measured plasma levels of total tau, pTau‐181, pTau‐217, pTau‐231, and N‐terminal tau (NTA‐tau). We evaluated the performances of plasma biomarkers to predict tau positivity in Aβ+ individuals.RESULTSHighest associations with tau positivity in Aβ+ individuals were found for plasma pTau‐217 (AUC [CI95%] = 0.89 [0.82, 0.96]) and NTA‐tau (AUC [CI95%] = 0.88 [0.91, 0.95]). Combining pTau‐217 and NTA‐tau resulted in the strongest agreement (Cohen's Kappa = 0.74, CI95% = 0.57/0.90, sensitivity = 92%, specificity = 81%) with PET for classifying tau positivity.DISCUSSIONThe potential for identifying tau accumulation in later Braak stages will be useful for patient stratification and prognostication in treatment trials and in clinical practice.Highlights We found that in a cohort without pre‐selection pTau‐181, pTau‐217, and NTA‐tau showed the highest association with tau PET positivity. We found that in Aβ+ individuals pTau‐217 and NTA‐tau showed the highest association with tau PET positivity. Combining pTau‐217 and NTA‐tau resulted in the strongest agreement with the tau PET‐based classification.

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CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer’s disease

Cited by 47 publications

References 51 publications

Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

Nanoscale imaging of pT217‐tau in aged rhesus macaque entorhinal and dorsolateral prefrontal cortex: Evidence of interneuronal trafficking and early‐stage neurodegeneration

Plasma pTau‐217 and N‐terminal tau (NTA) enhance sensitivity to identify tau PET positivity in amyloid‐β positive individuals

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