- July 30, 2025
- Christina Lill, et al., University of Munster
Topic/Product:
CNS Disease Panel 120
Disease Area:
Parkinson's Disease
Sample Type:
Plasma
Abstract
Parkinson’s disease (PD) remains incurable, with a long preclinical phase currently undetectable by existing methods. In the largest proteomic study in neurodegenerative diseases to date, we analyzed blood samples from ∼74,000 individuals across discovery and validation cohorts. In the EPIC4PD discovery case-cohort, large-scale profiling of 7,285 proteins (SomaScan-7K) in 4,538 initially unaffected participants (574 incident cases) identified 17 proteins that predict PD up to 28 years before diagnosis. Additional proteins revealed sex-specific effects and time-dependent effect trajectories, capturing disease progression before symptom onset. Replication in three prospective cohorts (n=64,856; 1,034 incident cases) confirmed at least 12 key pre-diagnostic biomarkers with strong evidence, including TPPP2, HPGDS, ALPL, MFAP5, OGFR, ACAD8, TCL1A, GPC4, GSTA3, LCN2, KRAS, and GJA1. Preclinical biomarkers showed 86% concordant effect directions in independent prevalent PD cases (n=2,592; p=1.6×10−19). Furthermore, in the longitudinal Tracking PD cohort (n=794), HPGDS and MFAP5 also predicted cognitive decline. Notably, several of the identified PD biomarkers overlapped with those for incident Alzheimer’s disease and amyotrophic lateral sclerosis, indicating shared molecular signatures. A machine learning-derived protein score improved PD risk prediction in external validation. This extensive proteomics effort identified novel, actionable biomarkers opening new avenues for early PD risk stratification and precision medicine.
Authors & Affiliations
Jan Homann¹, Alexander G. Smith²*, Sarah Morgan³*, Elisabet A. Frick⁴⁵*, Fangyu Liu⁶*, Vivian Viallon⁷*, Rashmi Maurya⁸, Roxanna Korologou-Linden⁹, Valerija Dobricic¹⁰, Olena Ohlei¹, Laura Deecke¹, Fatema Hajizadah³, Yujia Zhao¹¹, Fanny Artaud¹², Karl Smith-Byrne¹³, P. Martijn Kolijn¹¹, Jose Maria Huerta¹⁴¹⁵, Nils Winter¹⁶, Marcela Guevara¹⁵¹⁷¹⁸, Ana Jimenez-Zabala¹⁹²⁰, María José Sánchez¹⁵²¹²², Camino Trobajo-Sanmartín¹⁵¹⁷¹⁸, Natalia Cabrera-Castro¹⁴¹⁵, Ana Vinagre¹⁹²³, Dafina Petrova¹⁵²¹²²²⁴, Sabina Sieri²⁵, Tim J. Key¹³, Nick Wareham²⁶, Rudolph Kaaks²⁷, Ruth C. Travis¹³, Tim Hahn¹⁶, Susan Baker⁹, Sean M. Kelly²⁸, Roel Vermeulen¹¹²⁹, Susan Peters¹¹, Giovanna Masala³⁰, Carlotta Sacerdote³¹, Nancy Finkel³², The Global Neurodegeneration Proteomics Consortium (GNPC)$, Alexis Elbaz¹², Moritz Hess³³, Verena Katzke²⁶, Lars Bertram¹⁰, Vilmundur Gudnason⁴⁵, Oliver Robinson²⁹, Honglei Chen³⁴, Lefkos Middleton⁹, Laura M. Winchester⁸, Ioanna Tzoulaki², Valborg Gudmundsdottir⁴⁵, Keenan A. Walker³⁵, Pietro Ferrari⁷, Elio Riboli², Marc J. Gunter², and Christina M. Lill¹⁹
¹ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
² Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
³ Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Queen Mary University of London, London, UK
⁴ Icelandic Heart Association, Kopavogur, Iceland
⁵ Faculty of Medicine, Department of Health Sciences, University of Iceland, Reykjavik, Iceland
⁶ Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA
⁷ International Agency for Research on Cancer (IARC/WHO), Nutrition and Metabolism Branch, Lyon, France
⁸ Department of Psychiatry, University of Oxford, Oxford, UK
⁹ Ageing and Epidemiology Unit (AGE), School of Public Health, Imperial College London, London, UK
¹⁰ Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, Lübeck, Germany
¹¹ Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
¹² Université Paris-Saclay, UVSQ, Inserm, Gustave Roussy, CESP, Villejuif, France
¹³ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
¹⁴ Department of Epidemiology, Murcia Regional Health Council, Biomedical Research Institute of Murcia-IMIB, Murcia, Spain
¹⁵ Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
¹⁶ Institute of Translational Psychiatry, University of Münster, Münster, Germany
¹⁷ Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain
¹⁸ Navarre Institute for Health Research (IdiSNA), Pamplona, Spain
¹⁹ Biogipuzkoa Health Research Institute, San Sebastian, Gipuzkoa, Spain
²⁰ Ministry of Health of the Basque Government, Sub-Directorate for Public Health and Addictions of Gipuzkoa, San Sebastián, Gipuzkoa, Spain
²¹ Escuela Andaluza de Salud Pública (EASP), Granada, Spain
²² Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain
²³ Osakidetza Basque Health Service, Donostia University Hospital, Neurology Department, San Sebastián, Gipuzkoa, Spain
²⁴ Servicio de Oncología Médica, Hospital Universitario Virgen de las Nieves, Granada, Spain
²⁵ Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
²⁶ Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK
²⁷ Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
²⁸ NYU Langone Health, Department of Neurology, New York, NY, USA
²⁹ University Medical Centre Utrecht, Utrecht, The Netherlands
³⁰ Clinical Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy
³¹ Department of Health Sciences, University of Eastern Piedmont, Novara, Italy
³² Novartis, Cambridge, MA, USA
³³ Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
³⁴ Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA
³⁵ Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA