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High-sensitivity plasma proteomics reveals disease-specific signatures and predictive biomarkers of Alzheimer's disease phenotypes in a large mixed-dementia cohort
Gong K, Timsina J, Ali M, Chen Y, Liu M, Wang C, Pottier C, Feld GK et al.. Molecular neurodegeneration, 2025-11-17
Topic: Amyloid, tau and blood-test diagnosis
Novel plasma assays enabled accurate blood-based biomarkers for neurodegenerative diseases with minimally invasive options for clinical use. Large-scale studies encompassing multiple neurodegenerative diseases using novel multiplex platforms are essential to uncover disease-specific biomarkers and pathways. We generated and analyzed plasma biomarker data using the NULISAseq™ CNS Panel from 3,232 participants with Alzheimer disease (AD), Dementia with Lewy bodies (DLB), Frontotemporal dementia (FTD), Parkinson disease (PD) and cognitively unimpaired individuals, from the Charles F. and Joanne Knight Alzheimer Disease Research Center. We identified proteins associated with disease status and AD-related phenotypes (Clinical Dementia Rating®, CSF Aβ42/Aβ40, Amyloid-PET, and Tau-PET). These proteins were used to identify disease-specific biomarkers and perform pathway analyses. We identified 81 proteins associated with AD, 21 with DLB, four with FTD, and 52 with PD after multiple test correction. Disease comparison showed that PD and DLB had the highest similarity, followed by AD and DLB. Concurrently, each disease also presented disease-specific signatures. Some AD-specific proteins included p-tau217; MSLN and SAA1 were specific to DLB, and FLT1 and PARK7 to PD. We also identified eight proteins associated with Amyloid-PET, eight with Tau-PET, 14 with CSF Aβ42/40 ratio, and 72 with CDR, some of which were specific to each phenotype. We used a data-driven approach to identify the p-tau217 cut-off for biomarker positivity. Plasma p-tau217 achieved an AUC of 0.81 (95% CI: 0.79-0.83) for AD diagnosis and 0.96 (95% CI: 0.94-0.98) for Amyloid positivity. P-tau217 had 93.77% agreement with Amyloid-PET status. Proteins associated with AD were enriched in protein-lipid complex binding pathway, whereas PD associated proteins were enriched in laminin-related pathways. FTD associated proteins were enriched in cytoskeleton proteins. This is the largest plasma NULISA CNS study performed till date and covers the four major neurodegenerative diseases: AD, PD, DLB and FTD. We validated the high classification accuracy of the NULISA plasma p-tau217 and its strong correlation with Amyloid-PET status. We also identified disease-specific proteins that could enhance differential diagnosis. These findings highlight the potential of the NULISA platform as a reliable quantitative tool for research and clinical applications in neurodegenerative diseases.
Key findings
- We identified proteins associated with disease status and AD-related phenotypes (Clinical Dementia Rating®, CSF Aβ42/Aβ40, Amyloid-PET, and Tau-PET).
- We identified 81 proteins associated with AD, 21 with DLB, four with FTD, and 52 with PD after multiple test correction.
- Disease comparison showed that PD and DLB had the highest similarity, followed by AD and DLB.
- We also identified eight proteins associated with Amyloid-PET, eight with Tau-PET, 14 with CSF Aβ42/40 ratio, and 72 with CDR, some of which were specific to each phenotype.
- Proteins associated with AD were enriched in protein-lipid complex binding pathway, whereas PD associated proteins were enriched in laminin-related pathways.
Why it matters
Using a large mixed-dementia cohort, this study identified many plasma proteins associated with Alzheimer's and other neurodegenerative diseases and with Alzheimer-related brain measures. These findings are about developing blood-based biomarkers for diagnosis, not about treating, curing, or preventing the disease.
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Study details
- Participants3,232
- Effect size93.77%
- Evidence strengthLow
How this study scored 54/100
Published in a peer-reviewed journal. Scored zero for study design and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular neurodegeneration) |
| Journal's citation record | 2 / 4 | Molecular Neurodegeneration: journal h-index 164 (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 | 3 / 4 | 3,232 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| 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 10.2× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 2 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 | 4 / 4 | Last-listed author Carlos C Cruchaga: h-index 102 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Washington University in St. Louis: institution h-index 1,962 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41250190) |
| Free to read | 2 / 2 | Free to read |
| Total | 54 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1186/s13024-025-00909-x
- PubMed: 41250190
- Original source →
- Free full text: Molecular Neurodegeneration →
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
Gong, K., Timsina, J., Ali, M., Chen, Y., Liu, M., Wang, C., et al. (2025). High-sensitivity plasma proteomics reveals disease-specific signatures and predictive biomarkers of Alzheimer's disease phenotypes in a large mixed-dementia cohort. Molecular neurodegeneration. https://doi.org/10.1186/s13024-025-00909-x
Vancouver
Gong K, Timsina J, Ali M, Chen Y, Liu M, Wang C, et al. High-sensitivity plasma proteomics reveals disease-specific signatures and predictive biomarkers of Alzheimer's disease phenotypes in a large mixed-dementia cohort. Molecular neurodegeneration. 2025. doi:10.1186/s13024-025-00909-x. PMID: 41250190.
BibTeX
@article{gong2025-41250190,
author = {Gong, K. and Timsina, J. and Ali, M. and Chen, Y. and Liu, M. and Wang, C. and Pottier, C. and Feld, G. K. and others},
title = {{High-sensitivity plasma proteomics reveals disease-specific signatures and predictive biomarkers of Alzheimer's disease phenotypes in a large mixed-dementia cohort}},
journal = {Molecular neurodegeneration},
year = {2025},
doi = {10.1186/s13024-025-00909-x},
pmid = {41250190},
url = {https://doi.org/10.1186/s13024-025-00909-x}
}
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