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  • Review Article
  • Published:

An update on blood-based biomarkers for non-Alzheimer neurodegenerative disorders

Abstract

Cerebrospinal fluid analyses and neuroimaging can identify the underlying pathophysiology at the earliest stage of some neurodegenerative disorders, but do not have the scalability needed for population screening. Therefore, a blood-based marker for such pathophysiology would have greater utility in a primary care setting and in eligibility screening for clinical trials. Rapid advances in ultra-sensitive assays have enabled the levels of pathological proteins to be measured in blood samples, but research has been predominantly focused on Alzheimer disease (AD). Nonetheless, proteins that were identified as potential blood-based biomarkers for AD, for example, amyloid-β, tau, phosphorylated tau and neurofilament light chain, are likely to be relevant to other neurodegenerative disorders that involve similar pathological processes and could also be useful for the differential diagnosis of clinical symptoms. This Review outlines the neuropathological, clinical, molecular imaging and cerebrospinal fluid features of the most common neurodegenerative disorders outside the AD continuum and gives an overview of the current status of blood-based biomarkers for these disorders.

Key points

  • Neurodegenerative disorders are characterized by protein aggregation and other pathological processes, which can affect the composition of biofluids such as blood and cerebrospinal fluid (CSF).

  • Analysis of CSF and molecular imaging of the brain enable the stratification of patient populations on the basis of underlying pathology, but are limited as population screening tools.

  • Advances in ultra-sensitive immunoassays for the measurement of amyloid-β, neurofilament light chain, total tau and phosphorylated tau, as well as mass spectrometry-based methods for the measurement of amyloid-β, have demonstrated that a blood-based screening tool for Alzheimer disease is a realistic and plausible possibility.

  • Evidence now suggests that blood-based biomarkers could also be important for other common neurodegenerative disorders: for example, Lewy body dementia, atypical parkinsonian disorders and frontotemporal dementia.

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Fig. 1: Examples of PET and MRI scans from individuals with AD, bvFTD, CBS or PSP.
Fig. 2: Current strategies for blood-based biomarker discovery in neurodegenerative disorder research.

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Acknowledgements

The authors’ research is partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. H.Z. is a Wallenberg Academy Fellow supported by grants from the Swedish Research Council (2018-02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931) and the UK Dementia Research Institute at UCL. K.B. is supported by the Torsten Söderberg Foundation, Stockholm, Sweden. P.S. is a Wallenberg Clinical Scholar and is supported by the Swedish Foundation for Strategic Research and the Van Geest Foundation. T.H. is supported by the Hungarian Brain Research Program (2017-1.2.1-NKP-2017-00002). R.L.J. is supported by an Alzheimer’s Association Research Fellowship (AARF-16-443577). M.S. is supported by the Wallenberg Centre for Molecular and Translational Medicine, the Swedish Research Council, the Swedish Alzheimer’s Foundation, and AFTD UK. M.S.-C. received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action grant agreement no. 752310. N.J.A is supported by the Wallenberg Centre for Molecular and Translational Medicine.

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N.J.A. and D.A. provided the initial idea and outline of content for the manuscript. G.D.R. and R.L.J. provided imaging data for creation of Fig. 1. All authors contributed to the content of the article, and critically reviewed and edited the manuscript.

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Correspondence to Dag Aarsland.

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Competing interests

D.A. has received research support and/or honoraria from Astra-Zeneca, GE Health, H. Lundbeck and Novartis Pharmaceuticals, and served as paid consultant for Eisai, H. Lundbeck, Heptares, Mentis Cura and Sanofi. K.B. has served as a consultant or at advisory boards for Alector, Alzheon, Biogen, CogRx, Lilly, Novartis and Roche Diagnostics, all unrelated to the work presented in this paper. H.Z. has participated in scientific advisory boards for CogRx, Roche Diagnostics, Samumed and Wave, has given lectures in symposia sponsored by Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. M.S. has served on an advisory board for Servier. All other authors declare no competing interests.

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Glossary

Mass spectrometry

A sensitive technique used to detect, identify and quantify molecules on the basis of their mass-to-charge ratio.

Negative predictive value

The probability that individuals with a negative test result do not have the disease of interest.

Positive predictive value

The probability that individuals with a positive test result have the disease of interest.

Colorimetric enzyme-linked immunosorbent assay

A common protein analysis technique, usually conducted in a 96-well plate format, in which the antigen is stabilized on a solid surface and probed with a specific enzyme-conjugated antibody; the resulting enzymatic reaction is then measured with a chromogenic reporter.

Selection reaction monitoring

(SRM). A targeted mass spectrometry technique for the detection and quantification of specific predetermined analytes with known fragmentation properties.

Endophenotype

Any characteristic that is normally associated with a condition but is not a direct symptom of that condition.

Immunomagnetic reduction

(IMR). An immunoassay in which magnetic particles are coated with antibody and the reduction in the spin of the particles correlates with the amount of ligand bound.

Receiver operating characteristic

(ROC). The ROC curve is a plot of the true-positive rate against the false-positive rate for a diagnostic test. The area under the ROC curve indicates the accuracy of the test; values close to 1 mean that the test reliably distinguishes between the two conditions, whereas a value of 0.50 means that the test is no better than chance.

MicroRNA

(miRNA). Non-coding RNA molecules, generally 21 to 24 nucleotides in length, which are usually cleaved from a larger hairpin-containing RNA.

Random forest model

A machine learning algorithm that uses a collection of decision tree data structures to perform regression or classification.

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Ashton, N.J., Hye, A., Rajkumar, A.P. et al. An update on blood-based biomarkers for non-Alzheimer neurodegenerative disorders. Nat Rev Neurol 16, 265–284 (2020). https://doi.org/10.1038/s41582-020-0348-0

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