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Metabolic phenotyping reveals an emerging role of ammonia abnormality in Alzheimer’s disease

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Listed:
  • Tianlu Chen

    (Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Fengfeng Pan

    (Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Qi Huang

    (Fudan University)

  • Guoxiang Xie

    (Inc.)

  • Xiaowen Chao

    (Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Lirong Wu

    (Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Jie Wang

    (Fudan University)

  • Liang Cui

    (Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Tao Sun

    (Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Mengci Li

    (Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Ying Wang

    (Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Yihui Guan

    (Fudan University)

  • Xiaojiao Zheng

    (Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Zhenxing Ren

    (Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Yuhuai Guo

    (Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Lu Wang

    (University of Hong Kong)

  • Kejun Zhou

    (Inc.)

  • Aihua Zhao

    (Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Qihao Guo

    (Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Fang Xie

    (Fudan University)

  • Wei Jia

    (Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
    University of Hong Kong)

Abstract

The metabolic implications in Alzheimer’s disease (AD) remain poorly understood. Here, we conducted a metabolomics study on a moderately aging Chinese Han cohort (n = 1397; mean age 66 years). Conjugated bile acids, branch-chain amino acids (BCAAs), and glutamate-related features exhibited strong correlations with cognitive impairment, clinical stage, and brain amyloid-β deposition (n = 421). These features demonstrated synergistic performances across clinical stages and subpopulations and enhanced the differentiation of AD stages beyond demographics and Apolipoprotein E ε4 allele (APOE-ε4). We validated their performances in eight data sets (total n = 7685) obtained from Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Memory and Aging Project (ROSMAP). Importantly, identified features are linked to blood ammonia homeostasis. We further confirmed the elevated ammonia level through AD development (n = 1060). Our findings highlight AD as a metabolic disease and emphasize the metabolite-mediated ammonia disturbance in AD and its potential as a signature and therapeutic target for AD.

Suggested Citation

  • Tianlu Chen & Fengfeng Pan & Qi Huang & Guoxiang Xie & Xiaowen Chao & Lirong Wu & Jie Wang & Liang Cui & Tao Sun & Mengci Li & Ying Wang & Yihui Guan & Xiaojiao Zheng & Zhenxing Ren & Yuhuai Guo & Lu , 2024. "Metabolic phenotyping reveals an emerging role of ammonia abnormality in Alzheimer’s disease," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47897-y
    DOI: 10.1038/s41467-024-47897-y
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    References listed on IDEAS

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    1. Matthias Arnold & Kwangsik Nho & Alexandra Kueider-Paisley & Tyler Massaro & Kevin Huynh & Barbara Brauner & Siamak MahmoudianDehkordi & Gregory Louie & M. Arthur Moseley & J. Will Thompson & Lisa St , 2020. "Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
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