Pan-neurodegeneration proteomics reveals disease subtypes and molecular signatures.

Shrestha HK, Sun H, Yarbro JM, Lee D, Liu D, Wang E, McReynolds M, Zhang N, Xie B, Yang S, Yu K, Poudel S, Li Y, Yuan ZF, Kong D, Wang M, Wang Z, Niu M, Wang H, Zaman M, Wang J, Vanderwall DR, Sun Y, Wu Z, Chen PC, Bai B, High AA, Faura J, Liu C, Bennett DA, Johnson ECB, Seyfried NT, Levey AI, Haroutunian V, Serrano GE, Beach TG, DeTure M, Kanekiyo T, Petersen RC, Bu G, McLean PJ, Dickson DW, Rademakers R, Yu G, Wang X, Zhang B, Peng J.

Cell · 2026-03-23

Research overview

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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.

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