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A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer's disease
Oh HS, Urey DY, Karlsson L, Zhu Z, Shen Y, Farinas A, Timsina J, Duggan MR et al.. Nature medicine, 2025-03-31
Topic: Amyloid, tau and blood-test diagnosis
Rates of cognitive decline in Alzheimer's disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20-40% of the variance in AD-related cognitive impairment (CI). To discover novel biomarkers of CI in AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case-control cohorts. Synapse proteins emerged as the strongest correlates of CI, independent of Aβ and tau. Using machine learning, we derived the CSF YWHAG:NPTX2 synapse protein ratio, which explained 27% of the variance in CI beyond CSF pTau 181 :Aβ 42 , 11% beyond tau positron emission tomography, and 28% beyond CSF neurofilament, growth-associated protein 43 and neurogranin in Aβ + and phosphorylated tau + (A+T 1 +) individuals. CSF YWHAG:NPTX2 also increased with normal aging and 20 years before estimated symptom onset in carriers of autosomal dominant AD mutations. Regarding cognitive prognosis, CSF YWHAG:NPTX2 predicted conversion from A+T 1 + cognitively normal to mild cognitive impairment (standard deviation increase hazard ratio = 3.0, P = 7.0 × 10 -4 ) and A+T 1 + mild cognitive impairment to dementia (standard deviation increase hazard ratio = 2.2, P = 8.2 × 10 -16 ) over a 15-year follow-up, adjusting for CSF pTau 181 :Aβ 42 , CSF neurofilament, CSF neurogranin, CSF growth-associated protein 43, age, APOE4 and sex. We also developed a plasma proteomic signature of CI, which we evaluated in 13,401 samples, which partly recapitulated CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 as a robust prognostic biomarker for cognitive resilience versus AD onset and progression, highlight the potential of plasma proteomics in replacing CSF measurement and further implicate synapse dysfunction as a core driver of AD dementia.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Oh, H. S., Urey, D. Y., Karlsson, L., Zhu, Z., Shen, Y., Farinas, A., et al. (2025). A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer's disease. Nature medicine. https://doi.org/10.1038/s41591-025-03565-2
Vancouver
Oh HS, Urey DY, Karlsson L, Zhu Z, Shen Y, Farinas A, et al. A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer's disease. Nature medicine. 2025. doi:10.1038/s41591-025-03565-2. PMID: 40164724.
BibTeX
@article{oh2025-40164724,
author = {Oh, H. S. and Urey, D. Y. and Karlsson, L. and Zhu, Z. and Shen, Y. and Farinas, A. and Timsina, J. and Duggan, M. R. and others},
title = {{A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer's disease}},
journal = {Nature medicine},
year = {2025},
doi = {10.1038/s41591-025-03565-2},
pmid = {40164724},
url = {https://doi.org/10.1038/s41591-025-03565-2}
}
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Key findings
- Overall, our findings underscore CSF YWHAG:NPTX2 as a robust prognostic biomarker for cognitive resilience versus AD onset and progression, highlight the potential of plasma proteomics in replacing CSF measurement and further implicate synapse dysfunction as a core driver of AD dementia.
Why it matters
Using cerebrospinal fluid proteomics in 3,397 individuals, the ratio YWHAG:NPTX2 explained variance in cognitive impairment beyond amyloid-beta and tau measures and predicted conversion from cognitively normal to mild cognitive impairment and from mild cognitive impairment to dementia. It is described as a prognostic biomarker, not a treatment, cure, or prevention.
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Study details
- Study designcase-control study
- Participants3,397
- Evidence strengthModerate
How this study scored 77/100
Published in a top-tier journal, and it is a case-control study. Scored zero for effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature medicine) |
| Journal's citation record | 4 / 4 | Nature Medicine: journal h-index 763 (OpenAlex, 2026-10-29) |
| Study design | 6 / 12 | A case-control study |
| Strength of evidence | 3 / 5 | Rated “moderate” 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 | 3,397 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 | 5 / 7 | Cited 124 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 41.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 6 / 6 | Cited 77.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 6 other studies in this library |
| Still being cited | 3 / 4 | Cited 124 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Tony Wyss‐Coray: h-index 106 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Stanford University: institution h-index 2,684 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 28 institution(s) in 5 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40164724) |
| Free to read | 2 / 2 | Free to read |
| Total | 77 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/s41591-025-03565-2
- PubMed: 40164724
- Original source →
- Free full text: Nature Medicine →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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