Ali Muhammad, Erabadda Buddhiprabha, Chen Yike, Xu Ying, Gong Katherine, Liu Menghan, Pichet Binette Alexa, Timsina Jigyasha, Western Daniel, Yang Chengran, Heo Gyujin, Vogel Jacob W, Tijms Betty M, Krish Varsha, Imam Farhad, Hansson Oskar, Winchester Laura, Cruchaga Carlos
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA.
Nat Med. 2025 Jul 15. doi: 10.1038/s41591-025-03833-1.
Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD) and frontotemporal dementia (FTD), exhibit distinct yet overlapping pathological mechanisms. Leveraging large-scale plasma proteomics data from the Global Neurodegeneration Proteomics Consortium, we analyzed 10,527 plasma samples (1,936 AD, 525 PD, 163 FTD, 1,638 dementia and 6,265 controls) to identify disease-specific and shared proteins across NDs. We identified 5,187 proteins significantly associated with AD, 3,748 with PD and 2,380 with FTD that revealed both common and divergent proteomic signatures, which were confirmed by multiple analytical approaches and orthogonal validation. PD and FTD showed the highest overlap (r = 0.44) and AD and PD the least (r = 0.04). Immune system, glycolysis, and matrisome-related pathways were enriched across all NDs, while disease-specific pathways included apoptotic processes in AD, endoplasmic reticulum-phagosome impairment in PD and platelet dysregulation in FTD. Network analysis identified key upstream regulators (RPS27A in AD, IRAK4 in PD and MAPK1 in FTD) potentially driving these proteomic changes. These findings reveal distinct and shared mechanisms across NDs, highlighting potential regulatory proteins and pathways for diagnostic and therapeutic strategies in neurodegeneration.
神经退行性疾病（NDs），如阿尔茨海默病（AD）、帕金森病（PD）和额颞叶痴呆（FTD），表现出不同但又相互重叠的病理机制。利用全球神经退行性疾病蛋白质组学联盟的大规模血浆蛋白质组学数据，我们分析了10527份血浆样本（1936份AD、525份PD、163份FTD、1638份痴呆症样本和6265份对照样本），以确定NDs中疾病特异性和共享的蛋白质。我们鉴定出5187种与AD显著相关的蛋白质、3748种与PD显著相关的蛋白质和2380种与FTD显著相关的蛋白质，这些蛋白质揭示了共同和不同的蛋白质组学特征，这通过多种分析方法和正交验证得到了证实。PD和FTD的重叠度最高（r = 0.44），AD和PD的重叠度最低（r = 0.04）。免疫系统、糖酵解和基质相关途径在所有NDs中均富集，而疾病特异性途径包括AD中的凋亡过程、PD中的内质网-吞噬体损伤和FTD中的血小板失调。网络分析确定了可能驱动这些蛋白质组学变化的关键上游调节因子（AD中的RPS27A、PD中的IRAK4和FTD中的MAPK1）。这些发现揭示了NDs中不同和共享的机制，突出了神经退行性疾病诊断和治疗策略中潜在的调节蛋白和途径。
