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Blood phospho-tau in Alzheimer disease: analysis, interpretation, and clinical utility

Abstract

Well-authenticated biomarkers can provide critical insights into the biological basis of Alzheimer disease (AD) to enable timely and accurate diagnosis, estimate future burden and support therapeutic trials. Current cerebrospinal fluid and molecular neuroimaging biomarkers fulfil these criteria but lack the scalability and simplicity necessary for widespread application. Blood biomarkers of adequate effectiveness have the potential to act as first-line diagnostic and prognostic tools, and offer the possibility of extensive population screening and use that is not limited to specialized centres. Accelerated progress in our understanding of the biochemistry of brain-derived tau protein and advances in ultrasensitive technologies have enabled the development of AD-specific phosphorylated tau (p-tau) biomarkers in blood. In this Review we discuss how new information on the molecular processing of brain p-tau and secretion of specific fragments into biofluids is informing blood biomarker development, enabling the evaluation of preanalytical factors that affect quantification, and informing harmonized protocols for blood handling. We also review the performance of blood p-tau biomarkers in the context of AD and discuss their potential contexts of use for clinical and research purposes. Finally, we highlight outstanding ethical, clinical and analytical challenges, and outline the steps that need to be taken to standardize inter-laboratory and inter-assay measurements.

Key points

  • Blood p-tau181, p-tau217 and p-tau231 biomarkers that reflect brain tau and amyloid-β (Aβ) pathophysiology have been developed and validated.

  • The levels of p-tau species in blood increase with increasing Aβ accumulation and clinical severity in individuals with AD; these changes are absent in individuals with cognitive impairment not due to AD.

  • Blood concentration of p-tau is associated with, and predicts changes in, cerebrospinal fluid (CSF) and PET measures of Aβ, tau and neurodegeneration; ante-mortem blood p-tau concentration predicts definite neuropathological diagnosis several years later, outperforming clinical diagnosis during life.

  • Blood p-tau has potential uses for definitive and differential diagnosis in specialized care, for prescreening in primary care and therapeutic trials, and for population-based and epidemiological studies.

  • Future studies in real-world settings (for example, heterogeneous and diverse memory clinic cohorts) will show whether blood p-tau can serve as a stand-alone confirmatory biomarker or replace CSF or PET biomarkers in specific scenarios.

  • Outstanding challenges such as the need for analytical guidelines, inter-laboratory method comparison and standardization, cut-off value generation and validation, appropriate use criteria for clinical implementation, and consideration of the ethics of direct-to-consumer tests should be addressed to enable accelerated progress.

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Fig. 1: Molecular processing of tau in the brain and biofluids informs the development of blood p-tau biomarkers.
Fig. 2: Association of plasma p-tau181 with Aβ PET and tau PET load.
Fig. 3: Potential applications of blood p-tau biomarkers in primary and specialist care.
Fig. 4: Advantages of blood p-tau prescreening to recruit asymptomatic individuals for anti-AD clinical trials.

Data availability

The data used to generate the figures in Box 4 are available from the corresponding author on reasonable request. The data can also be directly requested from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, http://adni.loni.usc.edu) and the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, McGill University (https://triad.tnl-mcgill.com/).

Code availability

The R code used to generate the figures in Box 4 is available in the Supplementary Information accompanying this Review.

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Acknowledgements

T.K.K. was funded by the Swedish Research Council (Vetenskapsrådet #2021-03244), an Alzheimer’s Association Research Fellowship (#AARF-21-850325), the BrightFocus Foundation (#A2020812F), an International Society for Neurochemistry’s Career Development Grant, the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-930627), the Swedish Brain Foundation (Hjärnfonden; #FO2020-0240), the Swedish Dementia Foundation (Demensförbundet), the Swedish Parkinson Foundation (Parkinsonfonden), the Gamla Tjänarinnor Foundation, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Agneta Prytz-Folkes & Gösta Folkes Foundation (#2020-00124), the Gun and Bertil Stohnes Foundation, and the Anna Lisa and Brother Björnsson’s Foundation. N.J.A. was supported by the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-931009), Hjärnfonden and the Swedish Dementia Foundation (Demensförbundet). M.S.-C. receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 948677); the Instituto de Salud Carlos III (PI19/00155); and the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I). H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and the UK Dementia Research Institute at University College London. K.B. is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and the European Union Joint Programme on Neurodegenerative Disease Research (JPND2019-466-236). The funders had no role in data collection, analysis or decision to publish.

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H.Z, T.K.K., N.J.A. and K.B. researched data for the article, made a substantial contribution to discussion of content, wrote the article, and reviewed and edited the manuscript before submission. G.B., W.S.B, A.L.B, L.M.-G., J.L.-R., T.A.P, M.S.-C. and P.R.-N. researched data for the article, made a substantial contribution to discussion of content, and reviewed and edited the manuscript before submission.

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Correspondence to Henrik Zetterberg.

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Competing interests

H.Z. has served on scientific advisory boards for CogRx, Denali, Pinteon Therapeutics, Roche Diagnostics, Samumed, Siemens Healthineers and Wave, and has given lectures in symposia sponsored by Alzecure, Biogen and Fujirebio. H.Z. is also a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). K.B. has served as a consultant, on advisory boards, or on data monitoring committees for Abcam, Axon, Biogen, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). M.S.-C. has served as a consultant and on advisory boards for Roche Diagnostics International Ltd and has given lectures in symposia sponsored by Roche Diagnostics, S.L.U and Roche Farma, S.A. The other authors report no competing interests.

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Glossary

Fractions

Part of a whole; for example, the soluble and insoluble parts of tau together form the pool of tau in the brain.

Tryptic

Peptides generated after a longer peptide or protein is incubated with the enzyme trypsin, to cleave the molecule at the amino acids lysine or arginine except when followed by a proline.

Single molecule array (Simoa)

An ultrasensitive immunoassay technology platform that allows small quantities of target analytes to be detected in biological fluids (for example, blood) that are remote from the brain.

Ethylenediaminetetraacetic acid (EDTA)-plasma

A clear component of blood obtained by collecting whole blood into a tube containing a known concentration of the chelating agent and anticoagulant EDTA for a defined amount of time and centrifuging the mixture to separate the upper layer of plasma from the heavier cellular components.

Citrate-plasma

Blood matrix prepared by adding a clotting-preventing citrate compound to whole blood for a fixed amount of time, and centrifuging to separate the clear liquid layer from the cellular material.

Heparin-plasma

The clear liquid component of blood obtained by adding heparin salt anticoagulant to whole blood to induce the separation of the upper layer of interest from the more dense cellular components.

Aβ-positive

The state of having abnormal levels of amyloid plaques in the brain, as determined at autopsy or measured in vivo using Aβ PET or the CSF Aβ1–42 to Aβ1–40 ratio.

Aβ-negative

The state of having normal amounts of amyloid plaques in the brain, either determined post mortem or analysed using Aβ PET or the CSF Aβ1–42 to Aβ1–40 ratio according to predefined thresholds.

Round-robin studies

Interlaboratory studies in which the same tests are independently performed at multiple centres or laboratories on identical samples and the results compared to assess variability of the assay.

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Karikari, T.K., Ashton, N.J., Brinkmalm, G. et al. Blood phospho-tau in Alzheimer disease: analysis, interpretation, and clinical utility. Nat Rev Neurol (2022). https://doi.org/10.1038/s41582-022-00665-2

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