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Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes
Aitana Sogorb‐Esteve, Sophia Weiner, Joel Simrén, Imogen J. Swift, Martina Bocchetta, Emily G. Todd, David M. Cash, Arabella Bouzigues et al.. Science Translational Medicine, 2025-02-05
Topic: Brain proteins, microglia and lab models
We used an untargeted mass spectrometric approach, tandem mass tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the Genetic FTD Initiative were analyzed, including samples from 107 presymptomatic (44 C9orf72 , 38 GRN , and 25 MAPT ) and 55 symptomatic (27 C9orf72 , 17 GRN , and 11 MAPT ) mutation carriers as well as 76 mutation-negative controls (“noncarriers”). We found shared and distinct proteomic alterations in each genetic form of FTD. Among the proteins significantly altered in symptomatic mutation carriers compared with noncarriers, we found that a set of proteins including neuronal pentraxin 2 and fatty acid binding protein 3 changed across all three genetic forms of FTD and patients with Alzheimer’s disease from previously published datasets. We observed differential changes in lysosomal proteins among symptomatic mutation carriers with marked abundance decreases in MAPT carriers but not other carriers. Further, we identified mutation-associated proteomic changes already evident in presymptomatic mutation carriers. Weighted gene coexpression network analysis combined with gene ontology annotation revealed clusters of proteins enriched in neurodegeneration and glial responses as well as synapse- or lysosome-related proteins indicating that these are the central biological processes affected in genetic FTD. These clusters correlated with measures of disease severity and were associated with cognitive decline. This study revealed distinct proteomic changes in the CSF of patients with genetic FTD, providing insights into the pathological processes involved in the disease. In addition, we identified proteins that warrant further exploration as diagnostic and prognostic biomarker candidates.
Key findings
- We found shared and distinct proteomic alterations in each genetic form of FTD.
- Among the proteins significantly altered in symptomatic mutation carriers compared with noncarriers, we found that a set of proteins including neuronal pentraxin 2 and fatty acid binding protein 3 changed across all three genetic forms of FTD and patients with Alzheimer’s disease from previously published datasets.
- We observed differential changes in lysosomal proteins among symptomatic mutation carriers with marked abundance decreases in MAPT carriers but not other carriers.
- Weighted gene coexpression network analysis combined with gene ontology annotation revealed clusters of proteins enriched in neurodegeneration and glial responses as well as synapse- or lysosome-related proteins indicating that these are the central biological processes affected in genetic FTD.
- These clusters correlated with measures of disease severity and were associated with cognitive decline.
Why it matters
This proteomic analysis found shared and distinct cerebrospinal fluid protein alterations in each genetic form of frontotemporal dementia, with some changes already evident in presymptomatic mutation carriers. These findings may help identify proteins involved in neurodegeneration and glial responses, but no treatment or cure is reported.
Study details
- Participants238
- Evidence strengthLow
How this study scored 55/100
Published in a peer-reviewed journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Science Translational Medicine) |
| Journal's citation record | 3 / 4 | Science Translational Medicine: journal h-index 365 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 2 / 4 | 238 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 16 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 5.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 4 / 6 | Cited 9.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 3 other studies in this library |
| Still being cited | 2 / 4 | Cited 16 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Gabriel Miltenberger: h-index 20 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Centre National de la Recherche Scientifique: institution h-index 2,511 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 57 institution(s) in 12 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 39908349) |
| Free to read | 2 / 2 | Free to read |
| Total | 55 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1126/scitranslmed.adm9654
- PubMed: 39908349
- Original source →
- Free full text: Science Translational Medicine →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Sogorb‐Esteve, A., Weiner, S., Simrén, J., Swift, I. J., Bocchetta, M., Todd, E. G., et al. (2025). Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes. Science Translational Medicine. https://doi.org/10.1126/scitranslmed.adm9654
Vancouver
Sogorb‐Esteve A, Weiner S, Simrén J, Swift IJ, Bocchetta M, Todd EG, et al. Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes. Science Translational Medicine. 2025. doi:10.1126/scitranslmed.adm9654. PMID: 39908349.
BibTeX
@article{sogorbesteve2025-39908349,
author = {Sogorb‐Esteve, Aitana and Weiner, Sophia and Simrén, Joel and Swift, Imogen J. and Bocchetta, Martina and Todd, Emily G. and Cash, David M. and Bouzigues, Arabella and others},
title = {{Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes}},
journal = {Science Translational Medicine},
year = {2025},
doi = {10.1126/scitranslmed.adm9654},
pmid = {39908349},
url = {https://doi.org/10.1126/scitranslmed.adm9654}
}
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