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

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 Wang, Kejun Zhou, Aihua Zhao, Qihao Guo (), Fang Xie () and Wei Jia ()
Additional contact information
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

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47897-y

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