Plasma Proteomic Signatures Predict Incident Amyotrophic Lateral Sclerosis: A Prospective Study Stratified by C9orf72 Expansion.
- 1Department of Neurology and Institute of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- 2Mental Health Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- 3Department of Pathophysiology, West China College of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China.
Abstract
Background
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder for which reliable preclinical biomarkers to predict disease onset are currently lacking. Plasma proteomics offers a promising avenue for early detection. The identification of plasma proteins and pathways associated with incident ALS holds potential to improve early diagnosis, enable risk stratification and provide insights into disease mechanisms.Methods
Employing the Olink Explore platform, we quantified 2920 plasma proteins within a prospective cohort of UK Biobank participants. Multivariate Cox proportional hazards regression was utilized to identify proteins associated with incident generalized ALS, C9-ALS (C9orf72-associated ALS) and non-C9-ALS. Enrichment analysis was conducted to delineate the biological pathways implicated by the identified proteins. Associations between plasma protein levels and the age at onset (AAO) of ALS were assessed via linear regression, while a multivariate Cox model was employed to evaluate the relationships between protein levels and ALS survival. We subsequently assessed potential causal relationships using Mendelian randomization (MR) and colocalization and analysed protein cross-sectional temporal patterns in ALS.Results
In this prospective cohort study, we followed 52 584 participants from the UK Biobank for a mean of 11.8 years. During this period, 291 (0.55%) incident cases of ALS were identified, among whom 34 individuals carried the C9orf72 hexanucleotide repeat expansion mutation. Nine proteins demonstrated associations with all-type ALS risk (FDR < 0.05): NEFL (HR: 2.897), CSRP3 (HR: 1.233), MYBPC1 (HR: 1.352), MEGF10 (HR: 1.744), MYOM3 (HR: 1.289) and THBS4 (HR: 1.570) were identified as risk factors, whereas EGFLAM (HR: 0.402), ITGAV (HR: 0.284) and CD248 (HR: 0.573) exhibited protective effects. NEFL (HR: 2.742) and three additional proteins were primarily associated with non-C9-ALS, while only NEFL (HR: 4.403) and COL5A1 (HR: 3.072) showed significant associations with C9-ALS. When combined with age and sex, these proteins yielded area under the curve (AUC) values exceeding 0.750 for predicting ALS at 3, 5 and 10 years. Furthermore, elevated NEFL levels were correlated with an earlier onset of non-C9-ALS and began to increase approximately 9.27 years prior to diagnosis, reaching a peak 1-2 years before clinical presentation in non-C9ALS cases via cross-sectional temporal analysis. Pathway analysis implicated muscle-related, extracellular matrix, energy metabolism and inflammatory pathways.Conclusions
This investigation uncovers extensive alterations in plasma proteins associated with ALS risk, revealing potential novel biomarkers for both sporadic and C9orf72-linked forms of the disease. These results enhance our comprehension of early ALS pathogenesis and provide a foundation for subsequent biomarker identification and the development of targeted therapeutic strategies.
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BibTeX
@article{su2026plasma,
title = {{Plasma Proteomic Signatures Predict Incident Amyotrophic Lateral Sclerosis: A Prospective Study Stratified by C9orf72 Expansion.}},
author = {Wei-Ming Su and Qing-Qing Duan and Nan Zhang and Sheng-Yi He and Ru-Yin Liu and Xiang-Jin Wen and Xiao-Jing Gu and Yi Wang and Bei Cao and Yong-Ping Chen},
journal = {Journal of cachexia, sarcopenia and muscle},
year = {2026},
month = oct,
doi = {10.1002/jcsm.70405},
url = {https://europepmc.org/article/MED/42901869},
note = {CC BY},
}
RIS
TY - JOUR
TI - Plasma Proteomic Signatures Predict Incident Amyotrophic Lateral Sclerosis: A Prospective Study Stratified by C9orf72 Expansion.
AU - Wei-Ming Su
AU - Qing-Qing Duan
AU - Nan Zhang
AU - Sheng-Yi He
AU - Ru-Yin Liu
AU - Xiang-Jin Wen
AU - Xiao-Jing Gu
AU - Yi Wang
AU - Bei Cao
AU - Yong-Ping Chen
PY - 2026
DA - 2026/10/01
JO - Journal of cachexia, sarcopenia and muscle
DO - 10.1002/jcsm.70405
UR - https://europepmc.org/article/MED/42901869
AB - Background Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder for which reliable preclinical biomarkers to predict disease onset are currently lacking. Plasma proteomics offers a promising avenue for early detection. The identification of plasma proteins and pathways associated with incident ALS holds potential to improve early diagnosis, enable risk stratification and provide insights into disease mechanisms.Methods Employing the Olink Explore platform, we quantified 2920 plasma proteins within a prospective cohort of UK Biobank participants. Multivariate Cox proportional hazards regression was utilized to identify proteins associated with incident generalized ALS, C9-ALS (C9orf72-associated ALS) and non-C9-ALS. Enrichment analysis was conducted to delineate the biological pathways implicated by the identified proteins. Associations between plasma protein levels and the age at onset (AAO) of ALS were assessed via linear regression, while a multivariate Cox model was employed to evaluate the relationships between protein levels and ALS survival. We subsequently assessed potential causal relationships using Mendelian randomization (MR) and colocalization and analysed protein cross-sectional temporal patterns in ALS.Results In this prospective cohort study, we followed 52 584 participants from the UK Biobank for a mean of 11.8 years. During this period, 291 (0.55%) incident cases of ALS were identified, among whom 34 individuals carried the C9orf72 hexanucleotide repeat expansion mutation. Nine proteins demonstrated associations with all-type ALS risk (FDR < 0.05): NEFL (HR: 2.897), CSRP3 (HR: 1.233), MYBPC1 (HR: 1.352), MEGF10 (HR: 1.744), MYOM3 (HR: 1.289) and THBS4 (HR: 1.570) were identified as risk factors, whereas EGFLAM (HR: 0.402), ITGAV (HR: 0.284) and CD248 (HR: 0.573) exhibited protective effects. NEFL (HR: 2.742) and three additional proteins were primarily associated with non-C9-ALS, while only NEFL (HR: 4.403) and COL5A1 (HR: 3.072) showed significant associations with C9-ALS. When combined with age and sex, these proteins yielded area under the curve (AUC) values exceeding 0.750 for predicting ALS at 3, 5 and 10 years. Furthermore, elevated NEFL levels were correlated with an earlier onset of non-C9-ALS and began to increase approximately 9.27 years prior to diagnosis, reaching a peak 1-2 years before clinical presentation in non-C9ALS cases via cross-sectional temporal analysis. Pathway analysis implicated muscle-related, extracellular matrix, energy metabolism and inflammatory pathways.Conclusions This investigation uncovers extensive alterations in plasma proteins associated with ALS risk, revealing potential novel biomarkers for both sporadic and C9orf72-linked forms of the disease. These results enhance our comprehension of early ALS pathogenesis and provide a foundation for subsequent biomarker identification and the development of targeted therapeutic strategies.
SN - 2190-5991
SN - 2190-6009
ER -