Cerebrospinal fluid proteomic signatures in cognitively normal individuals identify distinct clusters linked to neurodegeneration

Topic/Product:
CNS Disease Panel 120, Neurology
Disease Area:
Alzheimer's Disease
Sample Type:
Plasma

Abstract

Age and APOE ε4 are major risk factors for Alzheimer’s disease (AD), while sex differences exist in disease prevalence and progression. Cerebrospinal fluid (CSF) proteomics can provide additional insights into brain aging and AD. To examine proteomic changes due to age, sex and apolipoprotein E (APOE) ε4 along with amyloid status before clinical AD occurs, we profiled 6,175 proteins in the CSF from 994 cognitively normal individuals aged 43–91 years. We identified and replicated 2,172 age-associated, 711 sex-associated, 193 APOE ε4-associated and 1,807 amyloid-associated proteins, with extensive overlap suggesting their interplay. These CSF-specific signatures were distinct from those in plasma. Network analysis revealed two proteomic modules—M2 (age-associated, sex-associated and amyloid-associated) and M6 (age-associated and sex-associated)—which were linked to neuropsychiatric and aging-related diseases. Together, our study provides proteomic changes during the early phase of AD, which may help identify new therapeutic targets of AD.

Authors & Affiliations

Dahun Seo¹², Anh N. Do¹³⁴, Gyujin Heo¹⁴, Jiseon Kwon¹⁴, Soomin Song¹⁴, Catherine Apio¹⁵, Cheolmin Matthew Lee¹⁶, Jigyasha Timsina¹⁴, Katherine Gong¹⁴, Yike Chen¹⁴, Menghan Liu¹⁴, Pat Kohlfeld¹⁴, John Budde¹⁴, Merce Boada⁷⁸, Adelina Orellana⁷, Maria Victoria Fernandez⁷, Agustin Ruiz⁷⁸⁹, John C. Morris¹⁰¹¹, Suzanne E. Schindler¹⁰¹¹, Laura Ibanez¹¹¹², Taesung Park²⁵, Carlos Cruchaga¹⁴¹⁰¹², and Yun Ju Sung¹³⁴

 

¹ NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA
² Department of Statistics, Seoul National University, Seoul, Korea
³ Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA
⁴ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
⁵ Interdisciplinary Programs in Bioinformatics, Seoul National University, Seoul, Korea
⁶ Health Sciences Integrated Program, Northwestern University, Chicago, IL, USA
⁷ Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain
⁸ Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), National Institute of Health Carlos III, Madrid, Spain
⁹ Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA
¹⁰ The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
¹¹ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
¹² Hope Center, Washington University School of Medicine, St. Louis, MO, USA

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.

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.