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Publication
Neuron

Large-scale CSF and plasma proteomics reveal immune, synaptic, and extracellular matrix disruptions across neurodegenerative diseases

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  • March 30, 2026
  • Carlos Cruchaga, et al., Washington University in St. Louis
Topic/Product:
CNS Disease Panel 120, Neurology
Disease Area:
Alzheimer's Disease, Frontal Temporal Dementia (FTD), Lewy Body Dementia, Parkinson's Disease
Sample Type:
CSF, Plasma

Abstract

Neurodegenerative diseases (NDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD), share overlapping clinical and pathological features. We analyzed cerebrospinal fluid (CSF) and plasma proteomes from 2,705 and 3,009 samples, respectively, across these NDs, identifying disease-specific and shared molecular signatures. CSF showed more disease-associated proteins than plasma, with AD and DLB exhibiting the strongest cross-tissue similarity. Pathway analyses revealed shared dysregulation of immune-related processes in CSF and plasma across the NDs, as well as disease-specific impairment of glycosylation and apoptotic pathways in AD; ATF4 and PERK signaling in PD; fibroblast growth factor receptor (FGFR) and interleukin signaling in DLB; and glycoprotein hormones disruption in FTD. We developed disease-specific predictive models showing high accuracy (area under the curve [AUC]: 0.81–0.95 in CSF and 0.80–0.89 in plasma). These findings reveal distinct and convergent mechanisms across NDs, highlighting potential biomarkers and pathways for diagnostic and therapeutic strategies in neurodegeneration.

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Authors & Affiliations

Muhammad Ali¹, Jigyasha Timsina¹, Ying Xu¹, Yike Chen¹, Katherine Gong¹, Daniel Western¹, Gyujin Heo¹, Menghan Liu¹, John Budde¹, Cyril Pottier², Suzanne E. Schindler², John C. Morris², David M. Holtzman², Raquel Puerta³, Amanda Cano³, Merce Boada³, Maria V. Fernandez³, Agustin Ruiz³, Miquel Aguilar⁴, Ignacio Alvarez⁴, Pau Pastor⁴, Joel S. Perlmutter², Meghan C. Campbell², Paul T. Kotzbauer², Hamilton Se-Hwee Oh⁵, Edward N. Wilson⁶, Yann Le Guen⁶, Knight Alzheimer Disease Research Center (Knight-ADRC), Alzheimer Disease Neuroimaging Initiative (ADNI), Fundació ACE Alzheimer Center Barcelona (FACE), Barcelona-1, Stanford Alzheimer Disease Research Center (Stanford-ADRC), The Global Neurodegeneration Proteomics Consortium (GNPC), Rawan Tarawneh⁷, Tony Wyss-Coray⁶, Yun Ju Sung¹, Laura Ibanez¹˒², and Carlos Cruchaga* ¹˒²˒⁸

¹ Department of Psychiatry, Washington University, St. Louis, MO 63110, USA
² Department of Neurology, Washington University, St. Louis, MO 63110, USA
³ ACE Alzheimer Center Barcelona, Barcelona, Spain
⁴ Fundació Docència i Recerca Mútua de Terrassa, Terrassa, Barcelona, Spain
⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
⁶ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA
⁷ Department of Neurology, Saint Louis University, St. Louis, MO 63110, USA
⁸ 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.