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[Preprint]. 2025 Jul 30:2025.07.30.25332433.

doi: 10.1101/2025.07.30.25332433.

Large-scale plasma proteomics uncovers preclinical molecular signatures of Parkinson's disease and overlap with other neurodegenerative disorders

Jan Homann¹, Alexander G Smith², Sarah Morgan³, Elisabet A Frick^{4

5}, 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 Huerta^{14

15}, Nils Winter¹⁶, Marcela Guevara^{15

17

18}, Ana Jimenez-Zabala^{19

20}, María José Sánchez^{15

21

22}, Camino Trobajo-Sanmartín^{15

17

18}, Natalia Cabrera-Castro^{14

15}, Ana Vinagre^{19

23}, Dafina Petrova^{15

21

22

24}, Sabina Sieri²⁵, Tim J Key¹³, Nick Wareham²⁶, Rudolph Kaaks²⁷, Ruth C Travis¹³, Tim Hahn¹⁶, Susan Baker⁹, Sean M Kelly²⁸, Roel Vermeulen^{11

29}, Susan Peters¹¹, Giovanna Masala³⁰, Carlotta Sacerdote³¹, Nancy Finkel³²; Global Neurodegeneration Proteomics Consortium (GNPC); Alexis Elbaz¹², Moritz Hess³³, Verena Katzke²⁶, Lars Bertram¹⁰, Vilmundur Gudnason^{4

5}, Oliver Robinson^{2

9}, Honglei Chen³⁴, Lefkos Middleton⁹, Laura M Winchester⁸, Ioanna Tzoulaki², Valborg Gudmundsdottir^{4

5}, Keenan A Walker⁶, Pietro Ferrari⁷, Elio Riboli², Marc J Gunter², Christina M Lill^{1

9}

Affiliations

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, Maryland, 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 Via Venezian, 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.
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, Germany.
³⁴ Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan, USA.

PMID: 40766128
PMCID: PMC12324616
DOI: 10.1101/2025.07.30.25332433

Large-scale plasma proteomics uncovers preclinical molecular signatures of Parkinson's disease and overlap with other neurodegenerative disorders

Jan Homann et al. medRxiv. 2025.

[Preprint]. 2025 Jul 30:2025.07.30.25332433.

doi: 10.1101/2025.07.30.25332433.

Authors

Affiliations

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, Maryland, 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 Via Venezian, 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.
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, Germany.
³⁴ Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan, USA.

PMID: 40766128
PMCID: PMC12324616
DOI: 10.1101/2025.07.30.25332433

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.

Keywords: EPIC; Parkinson’s disease; SomaLogic; aptamers; neurodegeneration; prediction; protein risk score; proteomics.

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Conflict of interest statement

Competing interests N.F. is an employee and stockholder of Novartis. K.A.W. is an Associate Editor at Alzheimer’s & Dementia, a member of the Editorial Board of Annals of Clinical and Translational Neurology, and on the Board of Directors of the National Academy of Neuropsychology. K.A.W. and I.W. have given unpaid seminars on behalf of SomaLogic. None of the other authors reports any competing interest.

Figures

**Figure 1.. Visual summary of study design.**
This study leveraged plasma proteomics from 4,538 individuals in the ‘European Prospective Investigation into Cancer and Nutrition for Parkinson’s disease’ case-cohort (EPIC4PD) to discover preclinical protein biomarkers of Parkinson’s disease (PD). Using the SomaScan 7K platform, 7,285 aptamers were analyzed across multiple time windows. Identified biomarkers were externally validated in three large cohorts (‘Age, Gene/Environment Susceptibility–Reykjavik Study’ [AGES], ‘Atherosclerosis Risk in Communities’ study [ARIC], and ‘United Kingdom Biobank’ [UKB]) and assessed in clinical PD cases from the ‘Global Neurodegenerative Proteomics Cohort’ [GNPC] and the longitudinal ‘Tracking Parkinson’s disease’ cohort. Functional characterization included pathway and cell-type enrichment, protein-protein networks, cross-trait analyses with Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). Predictive protein risk scores were calculated in EPIC4PD and externally validated in AGES.

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References

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This is a preprint.

Large-scale plasma proteomics uncovers preclinical molecular signatures of Parkinson's disease and overlap with other neurodegenerative disorders

Affiliations

Large-scale plasma proteomics uncovers preclinical molecular signatures of Parkinson's disease and overlap with other neurodegenerative disorders

Authors

Affiliations

Abstract

Conflict of interest statement

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