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Shared and disease-specific pathways in frontotemporal dementia and Alzheimer’s and Parkinson’s diseases

Ali, Muhammad ; Erabadda, Buddhiprabha ; Chen, Yike ; Xu, Ying ; Gong, Katherine ; Liu, Menghan ; Pichet Binette, Alexa LU ; Timsina, Jigyasha ; Western, Daniel and Yang, Chengran , et al. (2025) In Nature Medicine 31(8). p.2567-2577
Abstract

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 (r2 =... (More)

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 (r2 = 0.44) and AD and PD the least (r2 = 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.

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author collaboration
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type
Contribution to journal
publication status
published
subject
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Nature Medicine
volume
31
issue
8
pages
11 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:105013563194
  • pmid:40665052
ISSN
1078-8956
DOI
10.1038/s41591-025-03833-1
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.
id
cc6df072-130b-49f5-ae32-b85f6c82d684
date added to LUP
2025-11-07 12:54:04
date last changed
2025-12-19 17:28:12
@article{cc6df072-130b-49f5-ae32-b85f6c82d684,
  abstract     = {{<p>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<sup>2</sup> = 0.44) and AD and PD the least (r<sup>2</sup> = 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.</p>}},
  author       = {{Ali, Muhammad and Erabadda, Buddhiprabha and Chen, Yike and Xu, Ying and Gong, Katherine and Liu, Menghan and Pichet Binette, Alexa and Timsina, Jigyasha and Western, Daniel and Yang, Chengran and Heo, Gyujin and Vogel, Jacob W. and Tijms, Betty M. and Krish, Varsha and Imam, Farhad and Hansson, Oskar and Winchester, Laura and Cruchaga, Carlos}},
  issn         = {{1078-8956}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{2567--2577}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Medicine}},
  title        = {{Shared and disease-specific pathways in frontotemporal dementia and Alzheimer’s and Parkinson’s diseases}},
  url          = {{http://dx.doi.org/10.1038/s41591-025-03833-1}},
  doi          = {{10.1038/s41591-025-03833-1}},
  volume       = {{31}},
  year         = {{2025}},
}