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Original Investigation
July 28, 2020

Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders

Author Affiliations
  • 1Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden
  • 2Memory Clinic, Skåne University Hospital, Malmö, Sweden
  • 3Massachusetts General Hospital, Harvard Medical School, Boston
  • 4Grupo de Neurociencias de Antioquia of Universidad de Antioquia, Medellin, Colombia
  • 5Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
  • 6Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  • 7Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
  • 8UK Dementia Research Institute at UCL, London, United Kingdom
  • 9Banner Alzheimer’s Institute, Phoenix, Arizona
  • 10Banner Sun Health Research Institute, Sun City, Arizona
  • 11Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
  • 12Department of Neurology, Skåne University Hospital, Lund, Sweden
  • 13Molecular Neuropathology of Alzheimer’s Disease (MoNeA), Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 14Eli Lilly and Company, Indianapolis, Indiana
  • 15University of Arizona, Phoenix
  • 16Arizona State University, Phoenix
  • 17Translational Genomics Research Institute, Phoenix, Arizona
JAMA. Published online July 28, 2020. doi:10.1001/jama.2020.12134
Key Points

Question  What is the discriminative accuracy of plasma phospho-tau217 (P-tau217) for differentiating Alzheimer disease from other neurodegenerative disorders?

Findings  In this cross-sectional study that included 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated Alzheimer disease from other neurodegenerative diseases (area under the receiver operating characteristic curve of 0.89 in a neuropathologically defined cohort and 0.96 in a clinically defined cohort), with performance that was significantly better than established Alzheimer disease plasma- and MRI-based biomarkers but not significantly different from key CSF- or PET-based biomarkers.

Meaning  Although plasma P-tau217 was able to discriminate Alzheimer disease from other neurodegenerative diseases, further research is needed to validate the findings in unselected and diverse populations, optimize the assay, and determine its potential role in clinical care.

Abstract

Importance  There are limitations in current diagnostic testing approaches for Alzheimer disease (AD).

Objective  To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD.

Design, Setting, and Participants  Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017).

Exposures  Plasma P-tau217.

Main Outcomes and Measures  Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]).

Results  Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), β-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aβ42:Aβ40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22).

Conclusions and Relevance  Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care.

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