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Brain

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

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  • October 28, 2024
  • Oskiar Hansson, et al., Lund University
Topic/Product:
CNS Disease Panel 120, Neurology
Disease Area:
Alzheimer's Disease
Sample Type:
Plasma

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 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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Authors & Affiliations

Noëlle Warmenhoven¹, Gemma Salvadó¹, Shorena Janelidze¹, Niklas Mattsson-Carlgren¹²³, Divya Bali¹, Anna Orduña Dolado¹, Hartmuth Kolb⁴, Gallen Triana-Baltzer⁴, Nicolas R. Barthélemy⁵⁶, Suzanne E. Schindler⁶⁷⁸, Andrew J. Aschenbrenner⁶, Cyrus A. Raji⁷⁹, Tammie L. S. Benzinger⁷⁹, John C. Morris⁶⁷, Laura Ibanez¹⁰¹¹, Jigyasha Timsina¹⁰¹¹, Carlos Cruchaga¹⁰¹¹, Randall J. Bateman⁵⁶⁷⁸, Nicholas Ashton¹²¹³¹⁴¹⁵, Burak Arslan¹², Henrik Zetterberg¹²¹⁶¹⁷¹⁸¹⁹²⁰, Kaj Blennow¹²¹⁶, Alexa Pichet Binette¹, and Oskar Hansson¹²¹

¹ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö 211 46, Sweden
² Department of Neurology, Skåne University Hospital, Lund University, Malmö 205 02, Sweden
³ Wallenberg Center for Molecular Medicine, Lund University, Lund 223 62, Sweden
⁴ Neuroscience Biomarkers, Johnson & Johnson Innovative Medicine, San Diego, CA 92123, USA
⁵ The Tracy Family SILQ Center, Washington University School of Medicine, St. Louis, MO 63110, USA
⁶ Department of Neurology, Washington University School of Medicine, St. Louis, MO 63108, USA
⁷ Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO 63108, USA
⁸ Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63108, USA
⁹ Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA
¹⁰ Department of Psychiatry, Washington University, St. Louis, MO 63110, USA
¹¹ Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University, St. Louis, MO 63110, USA
¹² Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal 431 39, Sweden
¹³ King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute, London SE5 9RT, UK
¹⁴ NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia, South London and Maudsley NHS Foundation, London SE5 8AF, UK
¹⁵ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger 4011, Norway
¹⁶ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal 431 80, Sweden
¹⁷ Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK
¹⁸ UK Dementia Research Institute, University College London, London W1T 7NF, UK
¹⁹ Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Shatin, N.T., Hong Kong, China
²⁰ Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI 53792-2420, USA
²¹ Memory Clinic, Skåne University Hospital, Lund University, Malmö 205 02, Sweden

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Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

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Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition.  He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.