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Alzheimer's disease (AD), a neurodegenerative disorder, is the major form of dementia. As AD is an irreversible disease, it is necessary to focus on earlier intervention. However, the potential biomarkers of preclinical AD are still not clear. In this study, urinary metabolomics based on ultra-high-performance liquid chromatography coupled with quadruple time-of-flight mass spectrometry was performed for delineating the metabolic changes and potential early biomarkers in APPswe/PS1dE9 (APP/PS1) transgenic mice. A total of 24 differentially regulated metabolites were identified when comparing transgenic mice to wild-type mice using multivariate statistical analysis. Among them, 10 metabolites were significantly upregulated and 14 metabolites were downregulated. On the basis of these potential biomarkers, metabolic pathway analysis found that pentose and glucuronate interconversions, glyoxylate and dicarboxylate metabolism, starch and sucrose metabolism, the citrate cycle, tryptophan metabolism, and arginine and proline metabolism were disturbed in APP/PS1 mice. Our study revealed that levels of endogenous metabolites in the urine of APP/PS1 mice changed prior to the emergence of learning and cognitive impairment, which may be associated with abnormal nitric oxide production pathways and metabolic disorders of monoaminergic neurotransmitters. In conclusion, this study showed that metabolomics provides an early indicator of disease occurrence for AD.

Lipid metabolism has a significant function in the central nervous system and Alzheimer's disease (AD) is an age‐related senile disease characterized by central nerve degeneration. The pathological development of AD is closely related to lipid metabolism disorders. To reveal the influence of Kai‐Xin‐San (KXS) on lipid metabolism in APP/PSI transgenic mice and potential therapeutic targets for treating AD, brain tissue samples were collected and analyzed by high‐throughput lipidomics based on UPLC–Q/TOF‐MS. The collected raw data were processed by multivariate data analysis to discover the potential biomarkers and lipid metabolic profiles. Compared with the control wild‐type mouse group, nine potential lipid biomarkers were found in the AD model group, of which seven were up‐regulated and two were down‐regulated. Orally administrated KXS can reverse the changes in these potential biomarkers. Compared with the model group, a total of six differential metabolites showed a recovery trend and may be potential targets for KXS to treat AD. This study showed that high‐throughput lipidomics can be used to discover the perturbed pathways and lipid biomarkers as potential targets to reveal the therapeutic effects of KXS.