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Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration

Abstract

With the potential development of new disease-modifying Alzheimer’s disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid β positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid β-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.

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Fig. 1: Plasma pTau181 and plasma NfL per clinical diagnosis.
Fig. 2: Plasma pTau181 in pathology-confirmed cases and MAPT mutation carriers.
Fig. 3: Association of pTau181 and NfL, PiB-PET SUVR, FTP-PET SUVR and amyloid and FTP-PET status.
Fig. 4: Voxelwise correlations of plasma pTau181 and plasma NfL with FTP-PET and gray matter atrophy.

Data availability

All requests for raw and analyzed data and materials will be promptly reviewed by the corresponding author and the University of California, San Francisco to verify whether the request is subject to any intellectual property or confidentiality obligations. Some participant data not included in the paper were generated as part of clinical trials and may be subject to patient confidentiality limitations. Data and materials from participants with FTLD enrolled in ARTFL are accessible via forms that can be found on the ARTFL website (https://www.rarediseasesnetwork.org/cms/artfl/Healthcare-Professionals/Collaborating). Other data and materials that can be shared will be released via a material transfer agreement.

Code availability

All requests for code used for data analyses and data visualization will be promptly reviewed by the corresponding author and the UCSF to verify whether the request is subject to any intellectual property, confidentiality or other licensing obligations. If there are no limitations, the corresponding author will communicate with the requester to share the code.

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Acknowledgements

S. Lowe designed and conducted Eli Lilly’s study (NCT02624778) and provided a critical review of the manuscript. Data collection and dissemination of the data presented in this manuscript was supported by the LEFFTDS and ARTFL Consortium (LEFFTDS, U01 AG045390 (B.F.B. and H.R.)), funded by the National Institute on Aging and the National Institute of Neurological Diseases and Stroke (ARTFL, U54-NS092089 (A.L.B.)), part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Science (NCATS), and funded through a collaboration between NCATS and the National Institute of Neurological Disorders and Stroke, the Larry L. Hillblom Network and grant P01-AG019724-17 (B.L.M.). Samples from the National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886 (T. Foroud)), were used in this study. Imaging analyses were funded by the Tau Consortium, National Institute on Aging grants (R01-AG045611 (G.D.R.), P50-AG023501 (B.L.M.), P50-AG016574 (B.F.B.), P01-AG19724 (B.L.M.), R01-AG038791 (A.L.B.), U54-NS092089 (A.L.B.), State of California Department of Health Services Alzheimer’s Disease Research Center of California grant (04-33516 (B.L.M.)); Michael J. Fox Foundation (G.D.R.); Alzheimer’s Association (AARF-16-443577, R.L.J.) and K08AG052648 (S.S.). L.T.G. receives support from K24AG053435. J.C.R. receives support from K23AG059888. Avid Radiopharmaceuticals enabled use of the 18F-AV-1451 tracer by providing a precursor, but did not provide direct funding and was not involved in data analysis or interpretation. The funding agencies had no role in the design and conduct of the study, collection, management, analysis or interpretation of the data, preparation, review or approval of the manuscript or decision to submit the manuscript for publication.

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E.H.T. and J.C.R. had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. E.H.T., J.L.D., J.C.R. and A.L.B. were responsible for concept development and design. All authors contributed to acquisition, analysis or interpretation of data. E.H.T. drafted the manuscript. E.H.T., R.L.J., J.L.D., J.C.R. and A.L.B. critically revised the manuscript. E.H.T., R.L.J., P.W., D.C.A. and J.C.R. conducted statistical analyses. A.L.B., B.F.B., H.R., B.L.M., G.D.R., J.H.K. and J.L.D. obtained funding. J.L.D., J.C.R. and A.L.B. supervised the research.

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Correspondence to Adam L. Boxer.

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E.H.T, R.L.J., A.W., A.S., P.W., L.I., V.B., Y.C., H.H., S.S., A.M.K., C.E.T., J.H.K., W.W.S., H.R., B.F.B. and B.L.M. declare no conflict of interest. J.L.D., X.C., N.K.P., D.C.A., S.S., C.D.E. and J.R.S. are employees of Eli Lilly and Company. H.Z. has served on scientific advisory boards for Roche Diagnostics, Wave, Samumed and CogRx, has given lectures in symposia sponsored by Alzecure and Biogen and is a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. K.B. served as a consultant or on advisory boards for Alector, Biogen, CogRx, Eli Lilly, MagQu, Novartis and Roche Diagnostics and is a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg, all unrelated to the work presented in this paper. L.T.G. receives research support from Avid Radiopharmaceuticals and Eli Lilly. She has received consulting fees from the Simon Foundation and Cura Sen. She serves as Associate Editor for Frontiers in Aging Neurosciences, Frontiers in Dementia and the Journal of Alzheimer Disease. G.D.R. receives research support from the National Institutes of Health (NIH), Alzheimer’s Association, American College of Radiology, Tau Research Consortium, Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare and Life Molecular Imaging. He has served as a consultant for Eisai, Merck and Axon Neurosciences. He received speaking honoraria from GE Healthcare. He serves as Associate Editor for JAMA Neurology. J.C.R. is a Site Principal Investigator for clinical trials supported by Eli Lilly and receives support from NIH. A.L.B. receives research support from NIH, the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer’s Drug Discovery Foundation and the Alzheimer’s Association. He has served as a consultant for Aeton, Abbvie, Alector, AGTC, Amgen, Arkuda, Arvinas, Asceneuron, Eisai, Ionis, Lundbeck, Novartis, Passage BIO, Sangamo, Samumed, Third Rock, Toyama and UCB, and received research support from Avid, Biogen, BMS, C2N, Cortice, Eisai, Eli Lilly, Forum, Genentech, Janssen, Novartis, Pfizer, Roche and TauRx.

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Extended data

Extended Data Fig. 1 Plasma pTau/NfL ratio per clinical diagnosis.

The ratio of pTau181/NfL was decreased in all FTLD diagnoses compared to controls, ADclin and MCI patients (n=212). **p<0.001 *p<0.05.

Extended Data Fig. 2 Plasma Aβ 42/40 ratio per clinical diagnosis and Amyloid PET and FTP-PET status.

a. There was no difference in plasma Aβ 42/40 ratio between the different phenotypes(n=178). b. The Aβ 42/40 ratio was decreased in Amyloid PET positive cases (n=135). c. The Aβ 42/40 ratio was decreased in FTP-PET positive cases (n=76).

Extended Data Fig. 3 Plasma NfL concentrations per autopsy determined Braak stage.

There was no difference in plasma NfL concentrations between the different Braak stages (n=69).

Extended Data Fig. 4 Plasma pTau181 and plasma NfL concentrations in mutation carriers.

a. Plasma pTau181 concentrations did not differ between mutation carriers (n=120). b. Plasma NfL concentrations were elevated in GRN and C9orf72 mutation carriers compared to the control group (p<0.0001) and MAPT mutation carriers (p<0.01) (n=59). **p<0.01.

Extended Data Fig. 5 Association between plasma pTau181 and CSF pTau181.

CSF pTau181 is associated with plasma pTau181 (β=0.51, p<0.0001; n=74), and is also associated within the AD/MCI (β=0.41, p=0.042; n=25), and the FTLD group (β=0.49, p<0.0001; n=29), but not in controls.

Extended Data Fig. 6 Receiver Operating Characteristic analyses of plasma pTau181 for Aβ-PET status in MCI patients and in controls.

a. Plasma pTau181 concentrations are increased in Aβ-PET positive MCI cases. pTau181 could differentiate between Aβ-PET positive and negative cases (visual read). AUC=0.944 (95% CI: 0.873-1.000, p<0.0001, n= 18 Aβ-PET positive, 21 negative), with a cut-off of 8.4 pg/mL (0.944 sensitivity and 0.857 specificity). b. Plasma pTau181 concentrations are increased in Aβ-PET positive NC cases. pTau181 could differentiate between Aβ-PET positive and negative cases (visual read). AUC=0.859 (95% CI: 0.732-0.986, p=0.001, n=11 Aβ-PET positive, 29 negative), with a cut-off of 7.1 pg/mL (0.818 sensitivity and 0.828 specificity). Notch displays the confidence interval around the median. ***p<0.0001 **p<0.01.

Extended Data Fig. 7 Plasma pTau181 and plasma NfL concentrations per FTP-PET estimated Braak stage.

a. Plasma pTau181 was increased in Braak stage 5-6, and Braak stage 3-4 compared to Braak stage 0 (n=97). b. There was no difference in plasma NfL concentrations between the different Braak stages (n=61). ***p<0.0001.

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Thijssen, E.H., La Joie, R., Wolf, A. et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med 26, 387–397 (2020). https://doi.org/10.1038/s41591-020-0762-2

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