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Brain Communications

Identify biological Alzheimer’s disease using a novel nucleic acid-linked protein immunoassay

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  • January 7, 2025
  • Pedro Rosa-Neto, MD, PhD, et al., Translational Neuroimaging Laboratory, McGill Research Centre for Studies in Aging, Montreal Neurological Institute, Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University
Topic/Product:
CNS Disease Panel 120, Neurology
Disease Area:
Alzheimer's Disease
Sample Type:
Plasma

Abstract

Blood-based biomarkers have been revolutionizing the detection, diagnosis and screening of Alzheimer’s disease. Specifically, phosphorylated tau variants (p-tau181, p-tau217 and p-tau231) are promising biomarkers for identifying Alzheimer’s disease pathology. Antibody-based assays such as single molecule arrays immunoassays are powerful tools to investigate pathological changes indicated by blood-based biomarkers and have been studied extensively in the Alzheimer’s disease research field. A novel proteomic technology – NUcleic acid Linked Immuno-Sandwich Assay (NULISA) – was developed to improve the sensitivity of traditional proximity ligation assays and offer a comprehensive outlook for 120 protein biomarkers in neurodegenerative diseases. Due to the relative novelty of the NULISA technology in quantifying Alzheimer’s disease biomarkers, validation through comparisons with more established methods is required.

The main objective of the current study was to determine the capability of p-tau variants quantified using NULISA for identifying abnormal amyloid-β and tau pathology. We assessed 397 participants (mean [standard deviation] age, 64.8 [15.7] years; 244 females [61.5%] and 153 males [38.5%]) from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort where participants had plasma measurements of p-tau181, p-tau217 and p-tau231 from NULISA and single molecule arrays immunoassays. Participants also underwent neuroimaging assessments, including structural magnetic resonance imaging (MRI), amyloid and tau positron emission tomography (PET). Our findings suggest an excellent agreement between plasma p-tau variants quantified using NULISA and single molecule arrays immunoassays. Plasma p-tau217 measured with NULISA shows excellent discriminative accuracy for abnormal amyloid-PET (area under the receiver operating characteristic curve = 0.918, 95% confidence interval = 0.883 to 0.953, P < 0.0001) and tau-PET (area under the receiver operating characteristic curve = 0.939; 95% confidence interval = 0.909 to 0.969, P < 0.0001). It also presents the capability for differentiating tau-PET staging. Validation of the NULISA-measured plasma biomarkers adds to the current analytical methods for Alzheimer’s disease diagnosis, screening, and staging, and could potentially expedite the development of a blood-based biomarker panel.

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Authors & Affiliations

Yi-Ting Wang MSc1,2,3, Nicholas J. Ashton PhD4,5,6,7, Joseph Therriault PhD1,2, Andréa L. Benedet PhD4, Arthur C. Macedo MD1,2,3, Ilaria Pola MSc4, Etienne Aumont MSc1,2,3, Guglielmo Di Molfetta MSc4, Jaime FernandezArias MSc1,2,3, Kubra Tan PhD4, Nesrine Rahmouni MSc1,2,3, Stijn Johannes G. Servaes PhD1, Richard Isaacson MD, PhD8,9, Tevy Chan MD1,2, Seyyed Ali Hosseini MSc1,2,3, Cécile Tissot PhD10, Sulantha Mathotaarachchi MSc1, Jenna Stevenson BA1, Firoza Z Lussier MSc11, Tharick A. Pascoal MD PhD11, Serge Gauthier MD1,3, Kaj Blennow MD PhD4,12,13,14, Henrik Zetterberg MD PhD4,12,15,16,17,18, and Pedro Rosa-Neto MD, PhD1,2,3

  1. Translational Neuroimaging Laboratory, McGill Research Centre for Studies in Aging, Montreal, QC, Canada
  2. Montreal Neurological Institute, Montreal, QC, Canada
  3. Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, QC, Canada
  4. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
  5. Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway
  6. King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute, London, UK
  7. NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK
  8. Department of Neurology, Weill Cornell Medicine and New York – Presbyterian, New York, NY, USA
  9. Department of Neurology, Florida Atlantic University, Charles E. Schmidt College of Medicine, Boca Raton, FL, USA.
  10. Lawrence Berkeley National Laboratory, Berkeley, CA, USA
  11. Department of Neurology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  12. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  13. Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
  14. Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, China
  15. Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK
  16. UK Dementia Research Institute at UCL, London, UK
  17. Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China
  18. Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
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Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

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Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition.  He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.