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A comprehensive head-to-head comparison of key plasma phosphorylated tau 217 biomarker tests

Warmenhoven, Noëlle LU orcid ; Salvadó, Gemma LU ; Janelidze, Shorena LU ; Mattsson-Carlgren, Niklas LU orcid ; Bali, Divya LU ; Orduña Dolado, Anna LU ; Kolb, Hartmuth ; Triana-Baltzer, Gallen ; Barthélemy, Nicolas R. and Schindler, Suzanne E. , et al. (2025) In Brain 148(2). p.416-431
Abstract

Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarker for reliable detection of Alzheimer's disease pathology. Various p-tau217 assays have been developed, but their relative performance is unclear. We compared key plasma p-tau217 tests using cross-sectional and longitudinal measures of amyloid-β (Aβ)-PET, tau-PET and cognition as outcomes and benchmarked them against CSF biomarker tests. Samples from 998 individuals [mean (range) age 68.5 (20.0-92.5) years, 53% female] from the Swedish BioFINDER-2 cohort, including both cognitively unimpaired and cognitively impaired individuals, were analysed. Plasma p-tau217 was measured with mass spectrometry assays [the ratio between phosphorylated and... (More)

Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarker for reliable detection of Alzheimer's disease pathology. Various p-tau217 assays have been developed, but their relative performance is unclear. We compared key plasma p-tau217 tests using cross-sectional and longitudinal measures of amyloid-β (Aβ)-PET, tau-PET and cognition as outcomes and benchmarked them against CSF biomarker tests. Samples from 998 individuals [mean (range) age 68.5 (20.0-92.5) years, 53% female] from the Swedish BioFINDER-2 cohort, including both cognitively unimpaired and cognitively impaired individuals, were analysed. Plasma p-tau217 was measured with mass spectrometry assays [the ratio between phosphorylated and non-phosphorylated (%p-tau217WashU) and p-tau217WashU] and with immunoassays (p-tau217Lilly, p-tau217Janssen and p-tau217ALZpath). CSF biomarkers included p-tau217Lilly, the US Food and Drug Administration-approved p-tau181/Aβ42Elecsys, and p-tau181Elecsys. All plasma p-tau217 tests exhibited a high ability to detect abnormal Aβ-PET [area under the curve (AUC) range: 0.91-0.96] and tau-PET (AUC range: 0.94-0.97). Plasma %p-tau217WashU had the highest performance, with significantly higher AUCs than all the immunoassays (Pdiff < 0.007). For detecting Aβ-PET status, %p-tau217WashU had an accuracy of 0.93 (immunoassays: 0.83-0.88), sensitivity of 0.91 (immunoassays: 0.84-0.87) and a specificity of 0.94 (immunoassays: 0.85-0.89). Among immunoassays, p-tau217Lilly and plasma p-tau217ALZpath had higher AUCs than plasma p-tau217Janssen for Aβ-PET status (Pdiff < 0.006), and p-tau217Lilly outperformed plasma p-tau217ALZpath for tau-PET status (Pdiff = 0.025). Plasma %p-tau217WashU exhibited stronger associations with all PET load outcomes compared with immunoassays; baseline Aβ-PET load (R2: 0.72; immunoassays: 0.47-0.58; Pdiff < 0.001), baseline tau-PET load (R2: 0.51; immunoassays: 0.38-0.45; Pdiff < 0.001), longitudinal Aβ-PET load (R2: 0.53; immunoassays: 0.31-0.38; Pdiff < 0.001) and longitudinal tau-PET load (R2: 0.50; immunoassays: 0.35-0.43; Pdiff < 0.014). Among immunoassays, plasma p-tau217Lilly was more associated with Aβ-PET load than plasma p-tau217Janssen (Pdiff < 0.020) and with tau-PET load than both plasma p-tau217Janssen and plasma p-tau217ALZpath (all Pdiff < 0.010). Plasma %p-tau217 also correlated more strongly with baseline cognition (Mini-Mental State Examination) than all immunoassays (R2: %p-tau217WashU: 0.33; immunoassays: 0.27-0.30; Pdiff < 0.024). The main results were replicated in an external cohort from Washington University in St Louis (n = 219). Finally, p-tau217NULISA showed similar performance to other immunoassays in subsets of both cohorts. In summary, both mass spectrometry- and immunoassay-based p-tau217 tests generally perform well in identifying Aβ-PET, tau-PET and cognitive abnormalities, but %p-tau217WashU performed significantly better than all the examined immunoassays. Plasma %p-tau217 may be considered as a stand-alone confirmatory test for Alzheimer's disease pathology, whereas some immunoassays might be better suited as triage tests where positive results are confirmed with a second test, which needs to be determined by future reviews incorporating results from multiple cohorts.

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type
Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, CSF biomarkers, p-tau217, plasma biomarkers
in
Brain
volume
148
issue
2
pages
16 pages
publisher
Oxford University Press
external identifiers
  • scopus:85212769558
  • pmid:39468767
ISSN
0006-8950
DOI
10.1093/brain/awae346
language
English
LU publication?
yes
id
e373334e-efac-4f1e-8251-0379cea79767
date added to LUP
2025-12-19 12:56:59
date last changed
2025-12-20 03:46:49
@article{e373334e-efac-4f1e-8251-0379cea79767,
  abstract     = {{<p>Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarker for reliable detection of Alzheimer's disease pathology. Various p-tau217 assays have been developed, but their relative performance is unclear. We compared key plasma p-tau217 tests using cross-sectional and longitudinal measures of amyloid-β (Aβ)-PET, tau-PET and cognition as outcomes and benchmarked them against CSF biomarker tests. Samples from 998 individuals [mean (range) age 68.5 (20.0-92.5) years, 53% female] from the Swedish BioFINDER-2 cohort, including both cognitively unimpaired and cognitively impaired individuals, were analysed. Plasma p-tau217 was measured with mass spectrometry assays [the ratio between phosphorylated and non-phosphorylated (%p-tau217WashU) and p-tau217WashU] and with immunoassays (p-tau217Lilly, p-tau217Janssen and p-tau217ALZpath). CSF biomarkers included p-tau217Lilly, the US Food and Drug Administration-approved p-tau181/Aβ42Elecsys, and p-tau181Elecsys. All plasma p-tau217 tests exhibited a high ability to detect abnormal Aβ-PET [area under the curve (AUC) range: 0.91-0.96] and tau-PET (AUC range: 0.94-0.97). Plasma %p-tau217WashU had the highest performance, with significantly higher AUCs than all the immunoassays (Pdiff &lt; 0.007). For detecting Aβ-PET status, %p-tau217WashU had an accuracy of 0.93 (immunoassays: 0.83-0.88), sensitivity of 0.91 (immunoassays: 0.84-0.87) and a specificity of 0.94 (immunoassays: 0.85-0.89). Among immunoassays, p-tau217Lilly and plasma p-tau217ALZpath had higher AUCs than plasma p-tau217Janssen for Aβ-PET status (Pdiff &lt; 0.006), and p-tau217Lilly outperformed plasma p-tau217ALZpath for tau-PET status (Pdiff = 0.025). Plasma %p-tau217WashU exhibited stronger associations with all PET load outcomes compared with immunoassays; baseline Aβ-PET load (R2: 0.72; immunoassays: 0.47-0.58; Pdiff &lt; 0.001), baseline tau-PET load (R2: 0.51; immunoassays: 0.38-0.45; Pdiff &lt; 0.001), longitudinal Aβ-PET load (R2: 0.53; immunoassays: 0.31-0.38; Pdiff &lt; 0.001) and longitudinal tau-PET load (R2: 0.50; immunoassays: 0.35-0.43; Pdiff &lt; 0.014). Among immunoassays, plasma p-tau217Lilly was more associated with Aβ-PET load than plasma p-tau217Janssen (Pdiff &lt; 0.020) and with tau-PET load than both plasma p-tau217Janssen and plasma p-tau217ALZpath (all Pdiff &lt; 0.010). Plasma %p-tau217 also correlated more strongly with baseline cognition (Mini-Mental State Examination) than all immunoassays (R2: %p-tau217WashU: 0.33; immunoassays: 0.27-0.30; Pdiff &lt; 0.024). The main results were replicated in an external cohort from Washington University in St Louis (n = 219). Finally, p-tau217NULISA showed similar performance to other immunoassays in subsets of both cohorts. In summary, both mass spectrometry- and immunoassay-based p-tau217 tests generally perform well in identifying Aβ-PET, tau-PET and cognitive abnormalities, but %p-tau217WashU performed significantly better than all the examined immunoassays. Plasma %p-tau217 may be considered as a stand-alone confirmatory test for Alzheimer's disease pathology, whereas some immunoassays might be better suited as triage tests where positive results are confirmed with a second test, which needs to be determined by future reviews incorporating results from multiple cohorts.</p>}},
  author       = {{Warmenhoven, Noëlle and Salvadó, Gemma and Janelidze, Shorena and Mattsson-Carlgren, Niklas and Bali, Divya and Orduña Dolado, Anna and Kolb, Hartmuth and Triana-Baltzer, Gallen and Barthélemy, Nicolas R. and Schindler, Suzanne E. and Aschenbrenner, Andrew J. and Raji, Cyrus A. and Benzinger, Tammie L.S. and Morris, John C. and Ibanez, Laura and Timsina, Jigyasha and Cruchaga, Carlos and Bateman, Randall J. and Ashton, Nicholas and Arslan, Burak and Zetterberg, Henrik and Blennow, Kaj and Binette, Alexa Pichet and Hansson, Oskar}},
  issn         = {{0006-8950}},
  keywords     = {{Alzheimer's disease; CSF biomarkers; p-tau217; plasma biomarkers}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{416--431}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain}},
  title        = {{A comprehensive head-to-head comparison of key plasma phosphorylated tau 217 biomarker tests}},
  url          = {{http://dx.doi.org/10.1093/brain/awae346}},
  doi          = {{10.1093/brain/awae346}},
  volume       = {{148}},
  year         = {{2025}},
}