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Cited by 229Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCerebrospinal fluid and hydrocephalus

Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer's disease and PET amyloid-positive patient identification

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Barthélemy, Nicolas R., Bateman, Randall J., Hirtz, Christophe, Marin, Philippe, Becher, François, Sato, Chihiro, Gabelle, Audrey, Lehmann, Sylvain·2020·Alzheimer's Research & Therapy
DOI 10.1186/s13195-020-00596-4PMC PMC7079453
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Abstract

Background: Cerebrospinal fluid biomarker profiles characterized by decreased amyloid-beta peptide levels and increased total and phosphorylated tau levels at threonine 181 (pT181) are currently used to discriminate between Alzheimer’s disease and other neurodegenerative diseases. However, these changes are not entirely specific to Alzheimer’s disease, and it is noteworthy that other phosphorylated isoforms of tau, possibly more specific for the disease process, have been described in the brain parenchyma of patients. The precise detection of these isoforms in biological fluids remains however a challenge. Methods: In the present study, we used the latest quantitative mass spectrometry approach, which achieves a sensitive detection in cerebrospinal fluid biomarker of two phosphorylated tau isoforms, pT181 and pT217, and first analyzed a cohort of probable Alzheimer’s disease patients and patients with other neurological disorders, including tauopathies, and a set of cognitively normal controls. We then checked the validity of our results on a second cohort comprising cognitively normal individuals and patients with mild cognitive impairments and AD stratified in terms of their amyloid status based on PiB-PET imaging methods. Results: In the first cohort, pT217 but not pT181 differentiated between Alzheimer’s disease patients and those with other neurodegenerative diseases and control subjects much more specificity and sensitivity than pT181. T217 phosphorylation was increased by 6.0-fold in patients with Alzheimer’s disease whereas T181 phosphorylation was only increased by 1.3-fold, when compared with control subjects. These results were confirmed in the case of a second cohort, in which the pT217 cerebrospinal fluid levels marked out amyloid-positive patients with a sensitivity and a specificity of more than 90% (AUC 0.961; CI 0.874 to 0.995). The pT217 concentrations were also highly correlated with the PiB-PET values (correlation coefficient 0.72; P < 0.001). Conclusions: Increased cerebrospinal fluid pT217 levels, more than those of pT181, are highly specific biomarkers for detecting both the preclinical and advanced forms of Alzheimer’s disease. This finding should greatly improve the diagnosis of Alzheimer’s disease, along with the correlations found to exist between pT217 levels and PiB-PET data. It also suggests that pT217 is a promising potential target for therapeutic applications and that a link exists between amyloid and tau pathology.

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Authors
Barthélemy, N. R., Bateman, R. J., Hirtz, C., Marin, P., Becher, F., Sato, C., Gabelle, A., & Lehmann, S.
Affiliations
  • Inserm (FR)
  • Washington University in St. Louis (US)
  • Centre National de la Recherche Scientifique (FR)
  • Neuropsychiatrie : Recherche Epidemiologique et Clinique (FR)
Corresponding author
  • Barthélemy, Nicolas R.
  • Gabelle, Audrey
  • Lehmann, Sylvain
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2020-03-17
Volume
12
Issue
1
Pages
26-26
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-020-00596-4
PMC
PMC7079453
OpenAlex
W3011927235
Cited by
229
References
10
Citations by year
2026: 13 · 2025: 40 · 2024: 38 · 2023: 26 · 2022: 45 · 2021: 47 · 2020: 19
FWCI
21.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (NS065667, NS095773)
  • Direction de l’hospitalisation et de l’offre de Soins (PHRC-N-PROMARA-14-09)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
Keywords
Alzheimer's disease, phosphorylated tau, cerebrospinal fluid biomarkers, differential diagnosis, amyloid PET, PiB PET, tauopathy, mild cognitive impairment, preclinical Alzheimer's disease, sensitivity and specificity, neurodegenerative diseases
MeSH terms
Aged, Alzheimer Disease, Diagnosis, Differential, Female, Humans, Male, Peptide Fragments, Biomarkers, Amyloid beta-Peptides, tau Proteins, Positron-Emission Tomography

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