Him K. Shrestha, Huan Sun, Jay M. Yarbro, DongGeun Lee, Danting Liu, Erming Wang, Meghan McReynolds, Nan Zhang, Boer Xie, Shu Yang, Kaiwen Yu, Suresh Poudel, Yong Li, Zuo-Fei Yuan, Dehui Kong, Minghui Wang, Zhen Wang, Mingming Niu, H. J. Wang, Masihuz Zaman, Ju Wang, David Vanderwall, Yu Sun, Zhiping Wu, Ping-Chung Chen, Bing Bai, Anthony A. High, Júlia Faura, Chunyu Liu, David A. Bennett, Erik C.B. Johnson, Nicholas T. Seyfried, Allan I. Levey, Vahram Haroutunian, GE Serrano, Thomas G. Beach, Michael DeTure, Takahisa Kanekiyo, Ronald C. Petersen, GuoJun Bu, Pamela J. McLean, Dennis W. Dickson, Rosa Rademakers, Gang Yu, Xusheng Wang, Bin Zhang, Junmin Peng
Neurodegenerative diseases (NDs) pose clinical challenges due to their complexity and molecular heterogeneity. Here, we present a pan-neurodegeneration atlas (PanNDA) from multilayer, deep proteomic analysis of 2,279 human brain samples spanning 6 major NDs: Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal lobar degeneration with TDP-43 pathology, progressive supranuclear palsy with tau pathology, vascular dementia, and Parkinson's disease. PanNDA integrates data from whole proteome, detergent-insoluble proteome, and posttranslational modifications (phosphorylation and ubiquitination), enabling intra- and inter-disease comparisons. Intra-disease analyses uncover distinct molecular subtypes (e.g., three in AD and four in LBD), reveal dysregulated pathways, and prioritize top-ranked proteins. Inter-disease comparisons identify shared alterations in NDs, such as GPNMB in microglial and lysosomal activation and NPTX2 in synaptic regulation, alongside disease-specific changes and hub regulators within protein networks. Overall, PanNDA provides a systems-level framework for understanding ND mechanisms and serves as a foundational resource that is accessible via an interactive website: https://penglab.shinyapps.io/pannda.