Abstract
Identifying biomarkers that precisely track the neurodegenerative component of Alzheimer’s disease (AD) is essential for effective clinical management. Here we show that cerebrospinal fluid (CSF) levels of the synaptic proteins NPTX1 and NPTXR are robust indicators of disease severity and future clinical progression. In two independent, multi-ethnic cohorts spanning the AD continuum (n = 635), lower CSF NPTX levels correlate strongly with cognitive impairment and cortical thinning in AD-vulnerable regions. Longitudinally, baseline NPTX levels predict accelerated brain atrophy and the clinical transition from mild cognitive impairment to dementia, frequently outperforming or complementing established markers such as pTau181 and neurofilament light chain. These findings establish NPTX1 and NPTXR as sensitive, stage-specific markers of synaptic integrity and neurodegeneration. By accurately forecasting disease progression, these biomarkers offer significant potential to enhance patient stratification and provide a crucial tool for monitoring the efficacy of disease-modifying therapies in clinical trials.
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Based on the EU General Data Protection Regulation (GDPR) and the DDI Ethics Review Board provisions, anonymized aggregated-level data from DDI cohort will be shared by request from a qualified academic investigator for the sole purpose of replicating procedures and results presented in the article. Data transfer will comply with applicable regulations and relevant ethical review decisions. Source data for the main figures are provided with this paper. However, in accordance with the Regulations on the Management of Human Genetic Resources of China, individual-level clinical and genetic data from the Chinese (CANDI) cohort cannot be deposited in public repositories. Summary-level data and the findings supporting the study’s conclusions are available from the corresponding author upon reasonable request and subject to regulatory approval. Source data are provided with this paper.
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Acknowledgements
This work was supported by the National Natural Sciences Foundation of China (W2411069 and 82030034 to Y.S.; U23A20422 and 82501685 to L.D.; 82371418 and 82571610 to F.G.), the Chinese Academy of Sciences (XDB39000000 to Y.S.), the Fundamental Research Funds for the Central Universities (YD9110002027 and WK9100000057 to L.D.), Postdoctoral Science Foundation of Anhui Province (2023B723 to L.D.), Hefei Comprehensive National Science Center Hefei Brain Project (to Y.S.), the Major Frontier Research Project of the University of Science and Technology of China (LS9100000002 to Y.S.), USTC Research Funds of the Double First-Class Initiative (YD910002087 to F.G.), and the Norwegian Research Council (JPND/PMI-AD, NRC 311993 to T.F.).
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Y.S., K.B., F.G. and L.D. contributed to the conception and design of the study. L.D., C.W., M.Z., Q.W., M.N., B.E.K., F.G.-O., T.F. and J.S. contributed to the acquisition and analysis of data. L.D., F.G., B.E.K., F.G.-O., K.B. and Y.S. contributed to drafting the text or preparing the figures.
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B.E.K. has served as a consultant for Biogen and medical advisory boards for Biogen and Eli Lilly. T.F. has served as a consultant and at the advisory boards for Biogen, Eisai, Novo Nordisk, Eli Lilly and Roche. K.B. has served as a consultant and at advisory boards for AbbVie, AC Immune, ALZPath, AriBio, Beckman-Coulter, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Quanterix, Roche Diagnostics, Sunbird Bio, Sanofi and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. The remaining authors declare no competing interests
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Dai, L., Kirsebom, BE., Wang, C. et al. Cerebrospinal fluid NPTX1 and NPTXR predict neurodegeneration and clinical progression in Alzheimer’s disease. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70472-6
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DOI: https://doi.org/10.1038/s41467-026-70472-6
