Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Observational Study
. 2023 Feb 1;80(2):188-199.
doi: 10.1001/jamaneurol.2022.4485.

Association of Phosphorylated Tau Biomarkers With Amyloid Positron Emission Tomography vs Tau Positron Emission Tomography

Joseph Therriault  1   2 , Marie Vermeiren  1   3 , Stijn Servaes  1   2 , Cécile Tissot  1 , Nicholas J Ashton  4   5   6   7 , Andréa Lessa Benedet  4 , Thomas K Karikari  4   8 , Juan Lantero-Rodriguez  4 , Wagner S Brum  4   9 , Firoza Z Lussier  1   8 , Gleb Bezgin  1   2 , Jenna Stevenson  1 , Nesrine Rahmouni  1 , Peter Kunach  1   2 , Yi-Ting Wang  1   2 , Jaime Fernandez-Arias  1   2 , Kely Quispialaya Socualaya  1   2 , Arthur C Macedo  1   2 , João Pedro Ferrari-Souza  8 , Pâmela C L Ferreira  8 , Bruna Bellaver  8 , Douglas T Leffa  8 , Eduardo R Zimmer  9 , Paolo Vitali  2 , Jean-Paul Soucy  2 , Gallen Triana-Baltzer  10 , Hartmuth C Kolb  10 , Tharick A Pascoal  8 , Paramita Saha-Chaudhuri  11 , Serge Gauthier  1   2 , Henrik Zetterberg  4   12   13   14   15 , Kaj Blennow  4   12 , Pedro Rosa-Neto  1   2
Affiliations
Observational Study

Association of Phosphorylated Tau Biomarkers With Amyloid Positron Emission Tomography vs Tau Positron Emission Tomography

Joseph Therriault et al. JAMA Neurol. .

Abstract

Importance: The recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies of Alzheimer disease (AD): amyloid-β plaques and tau neurofibrillary tangles.

Objective: To determine whether cerebrospinal fluid (CSF) and plasma p-tau biomarkers preferentially reflect cerebral β-amyloidosis or neurofibrillary tangle aggregation measured with positron emission tomography (PET).

Design, setting, and participants: This was a cross-sectional study of 2 observational cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) study, with data collected between October 2017 and August 2021, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), with data collected between September 2015 and November 2019. TRIAD was a single-center study, and ADNI was a multicenter study. Two independent subsamples were derived from TRIAD. The first TRIAD subsample comprised individuals assessed with CSF p-tau (p-tau181, p-tau217, p-tau231, p-tau235), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. The second TRIAD subsample included individuals assessed with plasma p-tau (p-tau181, p-tau217, p-tau231), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. An independent cohort from ADNI comprised individuals assessed with CSF p-tau181, [18F]florbetapir PET, and [18F]flortaucipir PET. Participants were included based on the availability of p-tau and PET biomarker assessments collected within 9 months of each other. Exclusion criteria were a history of head trauma or magnetic resonance imaging/PET safety contraindications. No participants who met eligibility criteria were excluded.

Exposures: Amyloid PET, tau PET, and CSF and plasma assessments of p-tau measured with single molecule array (Simoa) assay or enzyme-linked immunosorbent assay.

Main outcomes and measures: Associations between p-tau biomarkers with amyloid PET and tau PET.

Results: A total of 609 participants (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) were included in the study. For all 4 phosphorylation sites assessed in CSF, p-tau was significantly more closely associated with amyloid-PET values than tau-PET values (p-tau181 difference, 13%; 95% CI, 3%-22%; P = .006; p-tau217 difference, 11%; 95% CI, 3%-20%; P = .003; p-tau231 difference, 15%; 95% CI, 5%-22%; P < .001; p-tau235 difference, 9%; 95% CI, 1%-19%; P = .02) . These results were replicated with plasma p-tau181 (difference, 11%; 95% CI, 1%-22%; P = .02), p-tau217 (difference, 9%; 95% CI, 1%-19%; P = .02), p-tau231 (difference, 13%; 95% CI, 3%-24%; P = .009), and CSF p-tau181 (difference, 9%; 95% CI, 1%-21%; P = .02) in independent cohorts.

Conclusions and relevance: Results of this cross-sectional study of 2 observational cohorts suggest that the p-tau abnormality as an early event in AD pathogenesis was associated with amyloid-β accumulation and highlights the need for careful interpretation of p-tau biomarkers in the context of the amyloid/tau/neurodegeneration, or A/T/(N), framework.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Karikari reported receiving a patent issued by H. Lundbeck A/S. Dr Wang reported receiving grants from Fonds de Recherche du Québec outside the submitted work. Dr Ferrari-Souza reported receiving grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico during the conduct of the study. Dr Zimmer reported receiving advisory board fees from Next Generation Therapeutics (Nintx) outside the submitted work. Dr Triana-Baltzer reported being an employee of Janssen R&D during the conduct of the study and having a patent for Plasma p217+tau assay pending. Dr Kolb reported being an employee of Janssen R&D during the conduct of the study and having a patent for p217Tau plasma assay pending. Dr Triana-Baltzar reported being an employee of Janssen R&D. Dr Gauthier reported receiving personal fees from Cerveau during the conduct of the study; being a scientific advisor to TauRx and AmyriAD; and being a lecturer on behalf of Biogen Canada, Lundbeck. Dr Zetterberg reported receiving advisory board fees or consultant fees from Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, CogRx, Eisai, Nervgen, AZTherapies, Red Abbey Labs, Alector, Triplet Therapeutics, ALZPath, AbbVie, Acumen, Annexon, Apellis, Artery Therapeutics, Novo Nordisk, Passage Bio, and reMYND; conducting a sponsored lecture for Cellectricon, Alzecure, Fujirebio, Biogen, and Roche; being cofounder of and having stock in Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program; and being an employee of Janssen R&D outside the submitted work. Dr Blennow reported receiving grants from the Swedish Alzheimer Foundation, Hjärnfonden, Sweden, the Swedish state under the agreement between the Swedish government and the County Councils, the ALF agreement, and the Alzheimer’s Association 2021 Zenith Award; and serving as a consultant, acted on advisory boards, or participated in data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers; and being a cofounder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program. Dr Rosa-Neto reported receiving consultant fees from Cerveau Radiopharmaceuticals. Drs Pascoal, Gauthier, and Rosa-Neto reported being members of the Canadian Institutes of Health Research and the Canadian Consortium of Neurodegeneration and Aging. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Association of Cerebrospinal Fluid (CSF) Phosphorylated Tau (p-Tau) Biomarkers With Amyloid Positron Emission Tomography (PET) and Tau PET Across the Cerebral Cortex
Brain images show the distribution of associations between CSF p-tau biomarkers (p-tau181, p-tau217, p-tau231, and p-tau235) and [18F]AZD4694 amyloid PET (A) and [18F]MK6240 tau PET (B). C, Density plots depict the magnitude and frequency of the correlations in voxels per CSF p-tau epitope and imaging biomarker. For all CSF p-tau phosphorylation sites, most voxels had correlation values with amyloid PET between 0.65 and 0.75. In contrast, the majority of voxels had correlations around 0.50 with tau PET, with limited numbers of voxels having correlations between 0.65 and 0.75.
Figure 2.
Figure 2.. Association of Cerebrospinal Fluid (CSF) Phosphorylated Tau (p-Tau) Biomarkers With Summary Amyloid Positron Emission Tomography (PET) and Tau PET Outcomes
Scatterplots show the association between CSF p-tau181, p-tau217, p-tau231, p-tau235, and summary measures of amyloid PET and tau PET in the Translational Biomarkers in Aging and Dementia study. ROI indicates region of interest; SUVR, standardized uptake value ratio.
Figure 3.
Figure 3.. Association of Cerebrospinal Fluid (CSF) Phosphorylated Tau (p-Tau)181 Biomarkers With Summary Amyloid Positron Emission Tomography (PET) and Tau PET in the Alzheimer’s Disease Neuroimaging Initiative
Scatterplots show the association between CSF p-tau181 and summary measures of [18F]florbetapir amyloid PET and [18F]flortaucipir tau PET in the Alzheimer Disease Neuroimaging Initiative study. ROI indicates region of interest; SUVR, standardized uptake value ratio.
Figure 4.
Figure 4.. Association of Plasma Phosphorylated Tau (p-Tau) Biomarkers With Amyloid Positron Emission Tomography (PET) and Tau PET
Scatterplots show the association between plasma p-tau181, p-tau217, p-tau231, and summary measures of amyloid PET and tau PET in the Translational Biomarkers in Aging and Dementia study. Brain images show the voxelwise associations of plasma p-tau181, p-tau217, and p-tau231 with [18F]AZD4694 standardized uptake value ratio (SUVR) and [18F]MK6240 SUVR. ROI indicates region of interest.
See this image and copyright information in PMC

References

    1. Montine TJ, Phelps CH, Beach TG, et al. ; National Institute on Aging; Alzheimer’s Association . National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol. 2012;123(1):1-11. doi: 10.1007/s00401-011-0910-3 - DOI - PMC - PubMed
    1. Hyman BT, Phelps CH, Beach TG, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 2012;8(1):1-13. doi: 10.1016/j.jalz.2011.10.007 - DOI - PMC - PubMed
    1. Jack CR Jr, Bennett DA, Blennow K, et al. A/T/N: an unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology. 2016;87(5):539-547. doi: 10.1212/WNL.0000000000002923 - DOI - PMC - PubMed
    1. Jack CR Jr, Bennett DA, Blennow K, et al. ; Contributors . NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562. doi: 10.1016/j.jalz.2018.02.018 - DOI - PMC - PubMed
    1. Rabinovici GD, Gatsonis C, Apgar C, et al. Association of amyloid positron emission tomography with subsequent change in clinical management among Medicare beneficiaries with mild cognitive impairment or dementia. JAMA. 2019;321(13):1286-1294. doi: 10.1001/jama.2019.2000 - DOI - PMC - PubMed

Publication types

LinkOut - more resources