A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer’s disease
Oh, Hamilton Se Hwee ; Urey, Deniz Yagmur ; Karlsson, Linda LU
; Zhu, Zeyu
; Shen, Yuanyuan
; Farinas, Amelia
; Timsina, Jigyasha
; Duggan, Michael R.
; Chen, Jingsha
and Guldner, Ian H.
, et al.
(2025)
In Nature Medicine
31.
p.1592-1603
- Abstract
- 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 pTau181:Aβ42, 11% beyond tau positron emission tomography, and 28%... (More)
- 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 pTau181:Aβ42, 11% beyond tau positron emission tomography, and 28% beyond CSF neurofilament, growth-associated protein 43 and neurogranin in Aβ+ and phosphorylated tau+ (A+T1+) 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+T1+ cognitively normal to mild cognitive impairment (standard deviation increase hazard ratio = 3.0, P = 7.0 × 10–4) and A+T1+ 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 pTau181:Aβ42, 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/baf05c16-51c3-400c-b13b-b6cdcb34bf26
- author
- Oh, Hamilton Se Hwee
; Urey, Deniz Yagmur
; Karlsson, Linda
LU
; Zhu, Zeyu
; Shen, Yuanyuan
; Farinas, Amelia
; Timsina, Jigyasha
; Duggan, Michael R.
; Chen, Jingsha
and Guldner, Ian H.
, et al. (More)
- Oh, Hamilton Se Hwee
; Urey, Deniz Yagmur
; Karlsson, Linda
LU
; Zhu, Zeyu
; Shen, Yuanyuan
; Farinas, Amelia
; Timsina, Jigyasha
; Duggan, Michael R.
; Chen, Jingsha
; Guldner, Ian H.
; Morshed, Nader
; Yang, Chengran
; Western, Daniel
; Ali, Muhammad
; Le Guen, Yann
; Trelle, Alexandra
; Herukka, Sanna-Kaisa
; Rauramaa, Tuomas
; Hiltunen, Mikko
; Lipponen, Anssi
; Luikku, Antti J.
; Poston, Kathleen L.
; Mormino, Elizabeth
; Wagner, Anthony D.
; Wilson, Edward N.
; Channappa, Divya
; Leinonen, Ville
; Stevens, Beth
; Ehrenberg, Alexander J.
; Gottesman, Rebecca F.
; Coresh, Josef
; Walker, Keenan A.
; Zetterberg, Henrik
; Bennett, David A.
; Franzmeier, Nicolai
; Hansson, Oskar
LU
; Cruchaga, Carlos
and Wyss-Coray, Tony
(Less)
- organization
- publishing date
- 2025-03-31
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Medicine
- volume
- 31
- pages
- 1592 - 1603
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:105001532220
- ISSN
- 1546-170X
- DOI
- 10.1038/s41591-025-03565-2
- language
- English
- LU publication?
- yes
- id
- baf05c16-51c3-400c-b13b-b6cdcb34bf26
- date added to LUP
- 2026-02-13 08:12:59
- date last changed
- 2026-02-14 04:01:13
@article{baf05c16-51c3-400c-b13b-b6cdcb34bf26,
abstract = {{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 pTau181:Aβ42, 11% beyond tau positron emission tomography, and 28% beyond CSF neurofilament, growth-associated protein 43 and neurogranin in Aβ+ and phosphorylated tau+ (A+T1+) 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+T1+ cognitively normal to mild cognitive impairment (standard deviation increase hazard ratio = 3.0, P = 7.0 × 10–4) and A+T1+ 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 pTau181:Aβ42, 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.}},
author = {{Oh, Hamilton Se Hwee and Urey, Deniz Yagmur and Karlsson, Linda and Zhu, Zeyu and Shen, Yuanyuan and Farinas, Amelia and Timsina, Jigyasha and Duggan, Michael R. and Chen, Jingsha and Guldner, Ian H. and Morshed, Nader and Yang, Chengran and Western, Daniel and Ali, Muhammad and Le Guen, Yann and Trelle, Alexandra and Herukka, Sanna-Kaisa and Rauramaa, Tuomas and Hiltunen, Mikko and Lipponen, Anssi and Luikku, Antti J. and Poston, Kathleen L. and Mormino, Elizabeth and Wagner, Anthony D. and Wilson, Edward N. and Channappa, Divya and Leinonen, Ville and Stevens, Beth and Ehrenberg, Alexander J. and Gottesman, Rebecca F. and Coresh, Josef and Walker, Keenan A. and Zetterberg, Henrik and Bennett, David A. and Franzmeier, Nicolai and Hansson, Oskar and Cruchaga, Carlos and Wyss-Coray, Tony}},
issn = {{1546-170X}},
language = {{eng}},
month = {{03}},
pages = {{1592--1603}},
publisher = {{Nature Publishing Group}},
series = {{Nature Medicine}},
title = {{A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer’s disease}},
url = {{http://dx.doi.org/10.1038/s41591-025-03565-2}},
doi = {{10.1038/s41591-025-03565-2}},
volume = {{31}},
year = {{2025}},
}