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medRxiv

Protein-based Diagnosis and Analysis of Co-pathologies Across Neurodegenerative Diseases: Large-Scale AI-Boosted CSF and Plasma Classification

  • July 10, 2025
  • Caros Cruchaga, et al., Washington University School of Medicine, St. Louis
Product:
CNS Disease Panel 120
Topic:
Neurology
Disease Area:
Neurodevelopmental Disabilities (NDD)
Sample Type:
CSF, Plasma
Back to Publications​
  • July 10, 2025
  • Caros Cruchaga, et al., Washington University School of Medicine, St. Louis
Topic/Product:
CNS Disease Panel 120
Disease Area:
Neurodevelopmental Disabilities (NDD)
Sample Type:
CSF, Plasma

Abstract

Neurodegenerative diseases (including Alzheimer’s disease, Parkinson’s disease, Frontotemporal dementia, and Dementia with Lewy bodies) pose diagnostic challenges due to overlapping pathology and clinical heterogeneity. We leveraged proteomic data from more than 21,000 cerebrospinal fluid and plasma samples to develop and validate explainable, boosting-based multi-disease AI classifiers. The models achieved weighted AUCs in the testing datasets of 0.97 for CSF and 0.88 for plasma, equivalent to traditional biomarkers. The model was validated with neuropathological and clinical data, confirming robust generalizability without any retraining. Using zero-shot learning, we classified disease subtypes including autosomal dominant AD and prodromal PD and clarified disease states for those with conflicting clinical information. The model also showed the ability to prioritize cognitively normal individuals at disease risk. This framework enabled the identification and quantification of continuous, individual-level disease probabilities that allow for the quantification of overlap across diseases and co-pathologies within an individual. Through this work, we establish a benchmark computational framework for enhancing diagnostic precision in NDs.

Read the pre-print

Authors & Affiliations

Ying Xu1,2,*, Daniel Western1,2,*, Gyujin Heo1,2, Kwangsik Nho3, Yen-Ning Huang3, Shiwei Liu3, Hamilton Se-Hwee Oh4,5,6,7, Yike Chen1,2, Jigyasha Timsina1,2, Menghan Liu1,2, Yinxu Tang8, Katherine Gong1,2, John Budde1,2, Varsha Krish9, Farhad Imam9, Raquel Puerta Fuentes10, Amanda Cano10,11, Marta Marquie10,11, Merce Boada10,11, Knight Alzheimer Disease Research Center (Knight-ADRC), Dominantly Inherited Alzheimer Network (DIAN), Alzheimer Disease Neuroimaging Initiative (ADNI), ACE Alzheimer Center Barcelona (ACE), Barcelona-1, Stanford Alzheimer Disease Research Center (Stanford-ADRC), The Global Neurodegeneration Proteomics Consortium (GNPC), Pau Pastor12, Agustin Ruiz10,11,13, Maria Victoria Fernández10, David Bennett14, Tony Wyss-Coray15, Andrew J Saykin3, Muhammad Ali1,2, Carlos Cruchaga1,2,16,17,18,19,†

Author Affiliations:

  1. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110
  2. NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO 63110
  3. Department of Radiology and Imaging Sciences, Indiana Alzheimer Disease Research Center, Indiana University School of Medicine, Indianapolis, Indiana USA
  4. Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  5. Brain and Body Research Center of the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  6. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  7. Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  8. Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130
  9. Gates Ventures, Seattle, WA, USA
  10. Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain
  11. CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
  12. Unit of Neurodegenerative diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain
  13. Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases and Department off Microbiology, Immunology, and Molecular Genetics, University of Texas Health Science Center, San Antonio, TX, USA
  14. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
  15. Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA
  16. Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110
  17. Department of Genetics, Washington University School of Medicine, St. Louis, 63110, MO, USA
  18. Hope Center for Neurological Disorders, Washington University, St. Louis, 63110, MO, USA
  19. Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110

*Authors with same contribution †Corresponding Author Email: cruchagac@wustl.edu

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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.