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Blood-based high sensitivity measurements of beta-amyloid and phosphorylated tau as biomarkers of Alzheimer’s disease: a focused review on recent advances
  1. Joyce R. Chong1,2,
  2. Nicholas J. Ashton3,4,5,6,
  3. Thomas K. Karikari6,7,
  4. Tomotaka Tanaka1,8,9,
  5. Michael Schöll3,6,10,
  6. Henrik Zetterberg6,10,11,12,
  7. Kaj Blennow6,12,
  8. Christopher P. Chen1,2,
  9. Mitchell K.P. Lai1,2
  1. 1Memory, Aging and Cognition Centre, National University Health Systems, Singapore
  2. 2Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  3. 3Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
  4. 4Psychology and Neuroscience, King's College London, Institute of Psychiatry, Maurice Wohl Institute Clinical Neuroscience Institute, London, UK
  5. 5NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia, South London and Maudsley NHS Foundation, London, UK
  6. 6Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
  7. 7Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  8. 8Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
  9. 9Clinical Imaging Research Centre, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  10. 10Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK
  11. 11Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden
  12. 12UK Dementia Research Institute at UCL, University College London, London, UK
  1. Correspondence to Dr Mitchell K.P. Lai, Department of Pharmacology, National University of Singapore, Unit 09-01, 14 Medical Drive, Kent Ridge 117599, Singapore; Mitchell.lai{at}


Discovery and development of clinically useful biomarkers for Alzheimer’s disease (AD) and related dementias have been the focus of recent research efforts. While cerebrospinal fluid and positron emission tomography or MRI-based neuroimaging markers have made the in vivo detection of AD pathology and its consequences possible, the high cost and invasiveness have limited their widespread use in the clinical setting. On the other hand, advances in potentially more accessible blood-based biomarkers had been impeded by lack of sensitivity in detecting changes in markers of the hallmarks of AD, including amyloid-β (Aβ) peptides and phosphorylated tau (P-tau). More recently, however, emerging technologies with superior sensitivity and specificity for measuring Aβ and P-tau have reported high concordances with AD severity. In this focused review, we describe several emerging technologies, including immunoprecipitation-mass spectrometry (IP-MS), single molecule array and Meso Scale Discovery immunoassay platforms, and appraise the current literature arising from their use to identify plaques, tangles and other AD-associated pathology. While there is potential clinical utility in adopting these technologies, we also highlight the further studies needed to establish Aβ and P-tau as blood-based biomarkers for AD, including validation with existing large sample sets, new independent cohorts from diverse backgrounds as well as population-based longitudinal studies. In conclusion, the availability of sensitive and reliable measurements of Aβ peptides and P-tau species in blood holds promise for the diagnosis, prognosis and outcome assessments in clinical trials for AD.

  • Alzheimer's disease
  • dementia
  • amyloid

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  • Contributors JCR, NA, TKK, TT, MS, HZ, KB, CL-HC and ML contributed to the conception and structure of the review, drafted the text and prepared the tables.

  • Funding This work is supported by the National Medical Research Council of Singapore (NMRC/CSA-SI/007/2016). TKK was funded by the BrightFocus Foundation (#A2020812F), the 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), 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. MS is supported by the Knut and Alice Wallenberg Foundation (Wallenberg Centre for Molecular and Translational Medicine Fellow; KAW 2014.0363), the Swedish Research Council (#2017-02869), and the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-813971) (all paid to the institution). HZ 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), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL.

  • Competing interests HZ has served at scientific advisory boards for Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies and CogRx, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Programme. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Prothena, 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 Programme.

  • Provenance and peer review Commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.