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Metagenomic analysis characterizes stage-specific gut microbiota in Alzheimer’s disease

Molecular Psychiatry volume 30, pages 3951–3962 (2025)Cite this article

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a decade-long preclinical pathological period that can be divided into several stages. Emerging evidence has revealed that the microbiota-gut-brain axis plays an important role in AD pathology. However, the role of gut microbiota in different AD stages has not been well characterized. In this study, we performed fecal shotgun metagenomic analysis on a Chinese cohort with 476 participants across five stages of AD pathology to characterize stage-specific alterations in gut microbiota and evaluate their diagnostic potential. We discovered extensive gut dysbiosis that is associated with neuroinflammation and neurotransmitter dysregulation, with over 10% of microbial species and gene families showing significant alterations during AD progression. Furthermore, we demonstrated that microbial gene families exhibited strong diagnostic capabilities, evidenced by an average AUC of 0.80 in cross-validation and 0.75 in independent external validation. In the optimal model, the most discriminant gene families are primarily involved in the metabolism of carbohydrates, amino acids, energy, glycan and vitamins. We found that stage-specific microbial gene families in AD pathology could be validated by an in vitro gut simulator and were associated with specific genera. We also observed that the gut microbiota could affect the progression of cognitive decline in 5xFAD mice through fecal microbiota transplantation, which could be used for early intervention of AD. Our multi-stage large cohort metagenomic analysis demonstrates that alterations in gut microbiota occur from the very early stages of AD pathology, offering important etiological and diagnostic insights.

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Fig. 1: Schematic workflow of this study.
Fig. 2: Differential taxonomic and functional signatures in Alzheimer’s disease progression.
Fig. 3: The performance of classifiers based on microbial species and functional modules.
Fig. 4: The most discriminant features in classifiers based on microbial KOs.
Fig. 5: Cognitive performance of the 5×FAD mice after fecal microbiota transplantation.

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Data availability

Shotgun metagenomic sequencing reads of our AD cohort is available in the China National Center for Bioinformation (CNCB) under accession number PRJCA022804. The publicly available Japan cohort can be accessed in the National Center for Biotechnology Information BioProject PRJNA679346. The five 16S rRNA amplicon sequencing datasets can be downloaded from the BioProject of NCBI: PRJNA489760, PRJNA554111, PRJNA633959, PRJNA734525, and PRJNA811324. The publicly available cohorts for other brain disorders can also be accessed in the BioProject of NCBI: PRJNA798058 for preclinical AD, PRJNA834801 for PD, PRJEB29127 for SCZ, and PRJNA516054, PRJEB23052 and PRJNA451479 for ASD. The publicly available BD cohort can be accessed in China National GeneBank DataBase (CNGBdb) with accession number CNP0002003.

Code availability

All custom code is available at the following GitHub repository: https://github.com/ZhaoXM-Lab/metaAD_analysis.

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Acknowledgements

The authors thank the patients and healthy participants who made this study possible and provided their fecal samples. This work was partly supported by National Natural Science Foundation of China (T2225015, 61932008, 62433008), Shanghai Science and Technology Commission Program (23JS1410100), Key Science and Technology Project of Hainan Province (ZDYF2024SHFZ058), National Key R&D Program of China (2023YFF1204800, 2020YFA0712403), Lingang Laboratory & National Key Laboratory of Human Factors Engineering Joint Grant (LG-TKN-202203-01) and Lingang Laboratory (LG-GG-202401-ADA010100 and LG-GG-202401-ADA050100). The computations in this research were performed using the CFFF platform of Fudan University.

Author information

Author notes

  1. These authors contributed equally: Longhao Jia, Yize Ke.

Authors and Affiliations

  1. Department of Neurology, Zhongshan Hospital and Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, 200433, China

    Longhao Jia, Jinxin Liu, Xiaohui Luo, Jixin Cao, Jianfeng Feng, Gunter Schumann, Tianye Jia, Qiang Luo, Jie Zhang, He Wang, Miao Cao, Xiao-Yong Zhang, Deniz Vatansever, Jingqi Chen, Xing-Ming Zhao, Jing Ding & Xing‑Ming Zhao

  2. Fudan Microbiome Center, State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, and Center for Obesity and Hernia Surgery, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Yize Ke & Hao Wu

  3. Laboratory of Molecular Neural Biology, School of Life Sciences, Shanghai University, Shanghai, 200444, China

    Shuo Zhao, Yujia Liu & Jiao Wang

  4. Department of Gerontology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China

    Qihao Guo

  5. Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular Imaging, Center for Artificial Intelligence Biology, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China

    Wei‑Hua Chen

  6. Institution of Medical Artificial Intelligence, Binzhou Medical University, Yantai, 264003, China

    Wei‑Hua Chen

  7. Department of Radiology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, Hainan, 570311, China

    Feng Chen

  8. Lingang Laboratory, Shanghai, 200031, China

    Xing-Ming Zhao & Xing‑Ming Zhao

  9. State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, 200032, China

    Xing-Ming Zhao & Xing‑Ming Zhao

  10. MOE Key Laboratory of Computational Neuroscience and Brain‑Inspired Intelligence, and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, China

    Jianfeng Feng, Jingqi Chen, Xing-Ming Zhao & Xing‑Ming Zhao

  11. Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, Zhejiang, 313000, China

    Xing-Ming Zhao & Xing‑Ming Zhao

  12. Medical Psychological Center, The Second Xiangya Hospital of Central South University, Changsha, 410011, China

    Shuqiao Yao & Xiang Wang

  13. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China

    Tianhong Zhang

  14. Psychiatry Department, Fudan University Affiliated Huashan Hospital, Shanghai, 200040, China

    Shenxun Shi

  15. Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Jijun Wang & Xin Wang

  16. Department of Neurology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Dezhi Liu

  17. Department of Vascular Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China

    Bo Yu

  18. Ministry of Education and Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China

    Fei Li

  19. Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Chunshui Yu

  20. Shanghai Key Laboratory of Magnetic Resonance, Department of Physics, East China Normal University, Shanghai, 200062, China

    Guang Yang

  21. Department of Biomedical Engineering, Chung Yuan Christian University, Taoyuan, Taiwan, 320314, China

    Chun-Yi Zac Lo

Authors
  1. Longhao Jia
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  2. Yize Ke
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  3. Shuo Zhao
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  4. Jinxin Liu
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  5. Xiaohui Luo
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  6. Jixin Cao
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  7. Yujia Liu
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  8. Qihao Guo
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  9. Wei‑Hua Chen
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  10. Feng Chen
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  11. Jiao Wang
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  12. Hao Wu
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  13. Jing Ding
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  14. Xing‑Ming Zhao
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Consortia

the ZIB Consortium

  • Longhao Jia
  • , Jinxin Liu
  • , Xiaohui Luo
  • , Jixin Cao
  • , Jianfeng Feng
  • , Gunter Schumann
  • , Tianye Jia
  • , Qihao Guo
  • , Shuqiao Yao
  • , Xiang Wang
  • , Tianhong Zhang
  • , Shenxun Shi
  • , Qiang Luo
  • , Jijun Wang
  • , Jie Zhang
  • , Xin Wang
  • , Jing Ding
  • , Dezhi Liu
  • , Bo Yu
  • , He Wang
  • , Fei Li
  • , Miao Cao
  • , Chunshui Yu
  • , Guang Yang
  • , Xiao-Yong Zhang
  • , Deniz Vatansever
  • , Jingqi Chen
  • , Chun-Yi Zac Lo
  •  & Xing-Ming Zhao

Contributions

XMZ and JD conceived the study and supervised the project. LHJ performed metagenomic analysis and wrote the first draft of the manuscript. QHG managed the sampling of fecal samples. YZK and HW conducted experimental validation by an in vitro intestinal simulator and fecal microbiota transplantation. SW, YJL, FC and JW performed behavioral monitoring based on novel object recognition and Y-maze tests. WHC and JXL provided useful suggestions. XHL and JXC helped curate metadata. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jiao Wang, Hao Wu, Jing Ding or Xing‑Ming Zhao.

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Jia, L., Ke, Y., Zhao, S. et al. Metagenomic analysis characterizes stage-specific gut microbiota in Alzheimer’s disease. Mol Psychiatry 30, 3951–3962 (2025). https://doi.org/10.1038/s41380-025-02973-7

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