Homann Jan, Korologou-Linden Roxanna, Viallon Vivian, Morgan Sarah, Dobricic Valerija, Deecke Laura, Schessner Julia P, Smith-Byrne Karl, Birtles Daniel, Zhao Yujia, Wuu Joanne, Artaud Fanny, Hajizadah Fatema, Huerta Jose Maria, Ohlei Olena, Lebedev Mikhail, Kolijn P Martijn, Guevara Marcela, Jimenez-Zabala Ana, Sánchez María José, Trobajo-Sanmartín Camino, Colorado-Yohar Sandra M, Alonso-Martín Sonia, Petrova Dafina, Sieri Sabina, Berger Klaus, Peters Susan, Wareham Nick, Kaaks Rudolph, Travis Ruth C, Vermeulen Roel C H, Tzoulaki Ioanna, Elbaz Alexis, Mann Matthias, Sacerdote Carlotta, Masala Giovanna, Katzke Verena, Benatar Michael, Bertram Lars, Middleton Lefkos, Riboli Elio, Gunter Marc J, Ferrari Pietro, Robinson Oliver, Lill Christina M
medRxiv. 2025 Aug 28:2025.08.20.25334061. doi: 10.1101/2025.08.20.25334061.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form.
We leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput proteomic profiling (7,285 protein markers, SomaScan). Cox proportional hazards models based on 4,567 participants (including 172 incident ALS cases) were used to identify protein biomarkers associated with future ALS diagnosis. Top results were indirectly validated in two independent case-control studies of prevalent ALS (n=417 ALS, 852 controls). Functional annotation included cross-disease comparisons, gene set and tissue enrichment testing, organ-specific proteomic clocks, and the application of large-language models (LLM).
Five proteins (SECTM1, CA3, THAP4, KLHL41, SLC26A7) were identified as significant pre-diagnostic ALS biomarkers (FDR=0.05), detectable approximately two decades before diagnosis. Of these, all except SECTM1 were indirectly validated in independent cohorts of prevalent ALS cases, supporting their clinical significance. Additionally, 22 nominally significant (p<0.05) pre-diagnostic biomarkers were FDR-significant in prevalent ALS with consistent effect directions. Cross-disease comparisons with pre-diagnostic Parkinson's and Alzheimer's disease suggested a largely specific pre-diagnostic ALS biomarker signature. Gene ontology and tissue enrichment highlighted early involvement of immune, muscle, metabolic, and digestive processes. Furthermore, analyses of proteomic clocks revealed accelerated aging in brain-cognition, immune, and muscle tissues before clinical diagnosis. Druggability and LLM analyses revealed possible therapeutic targets and novel strategies, emphasizing translational relevance.
Our study provides first evidence of ultra-early molecular changes in common ALS up to two decades prior to clinical onset, mainly affecting immune, muscle, metabolic, digestive, and cognitive systems. Our study nominates several compelling candidates for risk stratification studies and novel therapeutic targets for early intervention.
Clinical Research in ALS and Related Disorders for Therapeutic Development (CreATe) Consortium, Cure Alzheimer's Fund, Michael J Fox Foundation, Interdisciplinary Centre for Clinical Research, University Münster.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其诊断前阶段的病程和病理生理学在很大程度上尚不清楚，尤其是常见的非单基因形式。
我们利用欧洲癌症与营养前瞻性调查（EPIC）队列，该队列随访时间长达30年，以确定五个欧洲国家的ALS新发病例。对最初健康参与者的诊断前血浆样本进行高通量蛋白质组分析（7285种蛋白质标志物，SomaScan）。基于4567名参与者（包括172例ALS新发病例）的Cox比例风险模型用于识别与未来ALS诊断相关的蛋白质生物标志物。在两项独立的ALS现患病例对照研究（n = 417例ALS患者，852例对照）中对顶级结果进行了间接验证。功能注释包括跨疾病比较、基因集和组织富集测试、器官特异性蛋白质组时钟以及大语言模型（LLM）的应用。
五种蛋白质（SECTM1、CA3、THAP4、KLHL41、SLC26A7）被确定为诊断前显著的ALS生物标志物（FDR = 0.05），在诊断前约二十年即可检测到。其中，除SECTM1外，所有蛋白质在ALS现患病例的独立队列中均得到间接验证，支持了它们的临床意义。此外，22种名义上显著（p < 0.05）的诊断前生物标志物在ALS现患病例中FDR显著，且效应方向一致。与诊断前帕金森病和阿尔茨海默病的跨疾病比较表明，ALS诊断前生物标志物特征在很大程度上具有特异性。基因本体和组织富集突出了免疫、肌肉、代谢和消化过程的早期参与。此外，蛋白质组时钟分析显示，在临床诊断前，脑认知、免疫和肌肉组织出现加速衰老。药物可及性和LLM分析揭示了可能的治疗靶点和新策略，强调了转化相关性。
我们的研究首次证明了常见ALS在临床发病前长达二十年的超早期分子变化，主要影响免疫、肌肉、代谢、消化和认知系统。我们的研究为风险分层研究提名了几个有说服力的候选指标，并为早期干预提供了新的治疗靶点。
ALS及相关疾病治疗开发临床研究（CreATe）联盟、治愈阿尔茨海默病基金、迈克尔·J·福克斯基金会、明斯特大学跨学科临床研究中心。
