Abstract
Recent advances have identified YWHAG as a promising synaptic biomarker, with evidence showing that the YWHAG:NPTX2 ratio strongly predicts cognitive decline and Alzheimer’s disease (AD) progression independent of amyloid and tau pathology. However, the links between YWHAG and astrocytic processes-key regulators of amyloid clearance, tau phosphorylation, and neuroinflammation-remain poorly understood. A total of 530 participants were included. Levels of YWHAG and a panel of biologically relevant astrocyte-derived proteins were measured using a proximity extension assay and validated immunoassay platforms. Associations with AD biomarkers and cognition were examined using multivariable regression, longitudinal mixed-effects models, and mediation analyses. Path analysis was performed to explore the potential pathways from YWHAG through astrocytic proteins to AD pathology and cognition. We evaluated whether combining YWHAG with astrocyte-related proteins improves its predictive performance, by comparing the area under the curve (AUC) of the combined model with that of YWHAG alone. YWHAG was positively associated with glial fibrillary acidic protein (GFAP, β = 0.558, p < 0.001), vimentin (β = 0.329, p < 0.001), aquaporin-4 (AQP4, β = 0.097, p = 0.044), thrombospondin (THBS) -1 (β = 0.470, p < 0.001), and THBS2 (β = 0.285, p < 0.001), while showing negative associations with gap junction alpha-1 protein (GJα1, β = -0.161, p < 0.001) and serpin family A member 3 (SERPINA3, β = -0.350, p < 0.001). Mediation analysis indicated that certain astrocyte-related proteins may be involved in the association between YWHAG and AD pathology. Additionally, path analysis suggested a potential pathway involving YWHAG, GJα1, Aβ42, and cognitive function. The combination of YWHAG with SERPINA3 and THBS1 achieved an AUC of 0.981, outperforming YWHAG alone (AUC = 0.885). YWHAG is associated with astrocyte-related proteins, and combining them enhances its predictive accuracy for AD, highlighting its potential utility in early clinical screening.
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Data availability
Data used in this study were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (https://adni.loni.usc.edu). The ADNI is a publicly available dataset, and access is granted to qualified researchers upon application through the Laboratory of Neuro Imaging (LONI) Image and Data Archive (IDA). Researchers must comply with the ADNI Data Use Agreement and data sharing policies when accessing and using these data.
Code availability
The analytical code used in this study is not publicly available at this stage. Researchers with legitimate scientific purposes may request access to the code from the corresponding author, and the code can be shared upon reasonable request and mutual agreement.
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Acknowledgements
Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
Funding
This work was partially supported by the startup package and developmental funds of the First Affiliated Hospital of Nanchang University (#500021001, #500021002), National Natural Science Foundation (NSFC) (82471499), and Jiangxi Key Laboratory of Neurological Diseases (2024SSY06072) to WQZ; Cultivation Project of Jiangxi Medicine Academy of Nutrition and Health Management (2022-PYXM-02), the science and technology research project of Education Department of Jiangxi Province (GJJ2200101), and the Jiangxi Province 03 Special Project and 5 G Project (20232ABC03A23) to XH.
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ZH-Z designed the study, performed statistical analyses, interpreted the data, and drafted the manuscript. PC-H and YR-Y contributed to data analysis, data interpretation, and manuscript revision. HL-W and XR-Y participated in data collection and data curation. YF-W and K.N. contributed to statistical analysis, methodology development, and visualization. YJ-C and YH-W provided resources and assisted with data curation. ZY-C and PP-S contributed to data acquisition and validation. DJ-H supervised the study and contributed to project administration. X.H. and WQ-Z. conceived and supervised the study, secured funding, and critically revised the manuscript. All authors reviewed the manuscript and approved the final version.
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The study was approved by the Institutional Review Board of the University of Southern California and by the institutional review boards of all participating ADNI sites. Written informed consent was obtained from all participants or their authorized representatives in accordance with the Declaration of Helsinki.
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Zhang, Z., Huang, P., Yang, Y. et al. Astrocyte-related proteins mediate the association of YWHAG with Alzheimer’s pathology and enhance its diagnostic value. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-04020-7
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DOI: https://doi.org/10.1038/s41398-026-04020-7
