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CSF proteomics identifies early changes in autosomal dominant Alzheimer’s disease

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  • October 31, 2024
  • Carlos Cruchaga, et al - Washington University
Topic/Product:
CNS Disease Panel 120, Neurology
Disease Area:
Alzheimer's Disease
Sample Type:
CSF

Abstract

Highlights:

  • 137 CSF proteins’ trajectories differed between ADAD mutation carriers and non-carriers
  • The identified proteins started changing between 15 and 20 years before onset
  • The identified proteins are involved in neuronal death and immune pathways
  • Six proteins showed high predictive power for mutation and cognitive status

 

Summary:

In this high-throughput proteomic study of autosomal dominant Alzheimer’s disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for disease monitoring and treatment strategies. We examined CSF proteins in 286 mutation carriers (MCs) and 177 non-carriers (NCs). The developed multi-layer regression model distinguished proteins with different pseudo-trajectories between these groups. We validated our findings with independent ADAD as well as sporadic AD datasets and employed machine learning to develop and validate predictive models. Our study identified 137 proteins with distinct trajectories between MCs and NCs, including eight that changed before traditional AD biomarkers. These proteins are grouped into three stages: early stage (stress response, glutamate metabolism, neuron mitochondrial damage), middle stage (neuronal death, apoptosis), and late presymptomatic stage (microglial changes, cell communication). The predictive model revealed a six-protein subset that more effectively differentiated MCs from NCs, compared with conventional biomarkers.
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Authors & Affiliations

Yuanyuan Shen1,2,26 ∙ Jigyasha Timsina1,2,26 ∙ Gyujin Heo1,2 ∙ Aleksandra Beric1,2 ∙ Muhammad Ali1,2 ∙ Ciyang Wang1,2 ∙ Chengran Yang1,2 ∙ Yueyao Wang1,2 ∙ Daniel Western1,2 ∙ Menghan Liu1,2 ∙ Priyanka Gorijala1,2 ∙ John Budde1,2 ∙ Anh Do1,2 ∙ Haiyan Liu3 ∙ Brian Gordon3 ∙ Jorge J. Llibre-Guerra3 ∙ Nelly Joseph-Mathurin4 ∙ Richard J. Perrin5 ∙ Dario Maschi6 ∙ Tony Wyss-Coray7,8 ∙ Pau Pastor9 ∙ Alan E. Renton10,11,12 ∙ Ezequiel I. Surace13 ∙ Erik C.B. Johnson14,15 ∙ Allan I. Levey15 ∙ Ignacio Alvarez16 ∙ Johannes Levin17,18 ∙ John M. Ringman19 ∙ Ricardo Francisco Allegri20 ∙ Nicholas Seyfried21 ∙ Gregg S. Day22 ∙ Qisi Wu23 ∙ M. Victoria Fernández24 ∙ Rawan Tarawneh25 ∙ Eric McDade3 ∙ John C. Morris3 ∙ Randall J. Bateman3 ∙ Alison Goate10,11 ∙ Dominantly Inherited Alzheimer Network ∙ Laura Ibanez1,2,3 ∙ Yun Ju Sung1,2,3 ∙ Carlos Cruchaga1,2,3,27

  1. Department of Psychiatry, Washington University, St. Louis, MO 63110, USA
  2. NeuroGenomics and Informatics, Washington University, St. Louis, MO 63110, USA
  3. Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
  4. Mallinckrodt Institute of Radiology, Washington University St Louis, St Louis, MO 63110, USA
  5. Department of Pathology and Immunology, Washington University St. Louis, St. Louis, MO 63110, USA
  6. Department of Cell Biology and Physiology, Washington University St. Louis, St. Louis, MO 63110, USA
  7. Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA
  8. Department of Neurology & Neurological Sciences, Stanford University, Stanford, CA 94305, USA
  9. Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP), Badalona, Barcelona 08916, Spain
  10. Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
  11. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
  12. Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
  13. Laboratory of Neurodegenerative Diseases, Institute of Neurosciences (INEU-Fleni-CONICET), Buenos Aires, Argentina
  14. Goizueta Alzheimer’s Disease Research Center, Emory University School of Medicine, Atlanta, GA 30307, USA
  15. Department of Neurology, Emory University School of Medicine, Atlanta, GA 30307, USA
  16. Department of Neurology, University Hospital Mútua de Terrassa and Fundació Docència i Recerca Mútua de Terrassa, Terrassa 08221, Barcelona, Spain
  17. Department of Neurology, LMU University Hospital, LMU Munich, Munich 80336, Germany
  18. German Center for Neurodegenerative Diseases, site Munich, Munich 80336, Germany
  19. Alzheimer’s Disease Research Center, Department of Neurology, Keck School of Medicine at USC, Los Angeles, CA 90033, USA
  20. Department of Cognitive Neurology, Neuropsychology and Neuropsychiatry, FLENI, Buenos Aires, Argentina
  21. Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30307, USA
  22. Department of Neurology, Mayo Clinic in Florida, Jacksonville, FL 32224, USA
  23. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
  24. Fundacio ACE Institut de Neurosciencies Aplicades, Barcelona 08029, Spain
  25. The University of New Mexico, Albuquerque, NM 87131, USA
     
  26. These authors contributed equally
  27. Lead contact
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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.