Large-scale CSF and plasma proteomics reveal immune, synaptic, and extracellular matrix disruptions across neurodegenerative diseases

Neuron
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Muhammad Ali, Jigyasha Timsina, Ying Xu, Yike Chen, Katherine Gong, Daniel Western, Gyujin Heo, Menghan Liu, John Budde, Cyril Pottier, Suzanne E Schindler, John C Morris, David M Holtzman, Raquel Puerta, Amanda Cano, Merce Boada, Maria V Fernandez, Agustin Ruiz, Miquel Aguilar, Ignacio Alvarez, Pau Pastor, Joel S Perlmutter, Meghan C Campbell, Paul T Kotzbauer, Hamilton Se-Hwee Oh, Edward N Wilson, Yann Le Guen, Knight Alzheimer Disease Research Center (Knight-ADRC), Alzheimer Disease Neuroimaging Initiative (ADNI), Fundació ACE Alzheimer Center Barcelona (FACE), Barcelona-1, Stanford Alzheimer Disease Research Center (Stanford-ADRC), Global Neurodegeneration Proteomics Consortium (GNPC), Rawan Tarawneh, Tony Wyss-Coray, Yun Ju Sung, Laura Ibanez, Carlos Cruchaga

Neuron. 2026 Mar 30:S0896-6273(26)00140-6. doi: 10.1016/j.neuron.2026.02.035. Online ahead of print.

ABSTRACT

Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD), share overlapping clinical and pathological features. We analyzed cerebrospinal fluid (CSF) and plasma proteomes from 2,705 and 3,009 samples, respectively, across these NDs, identifying disease-specific and shared molecular signatures. CSF showed more disease-associated proteins than plasma, with AD and DLB exhibiting the strongest cross-tissue similarity. Pathway analyses revealed shared dysregulation of immune-related processes in CSF and plasma across the NDs, as well as disease-specific impairment of glycosylation and apoptotic pathways in AD; ATF4 and PERK signaling in PD; fibroblast growth factor receptor (FGFR) and interleukin signaling in DLB; and glycoprotein hormones disruption in FTD. We developed disease-specific predictive models showing high accuracy (area under the curve [AUC]: 0.81-0.95 in CSF and 0.80-0.89 in plasma). These findings reveal distinct and convergent mechanisms across NDs, highlighting potential biomarkers and pathways for diagnostic and therapeutic strategies in neurodegeneration.

PMID:41916283 | PMC:PMC13052424 | DOI:10.1016/j.neuron.2026.02.035