Serum metabolomic profiling following cerebellar repetitive transcranial magnetic stimulation combined with cognitive training on Alzheimer's disease.

BACKGROUND: Complex metabolic disorders are a key characteristic of Alzheimer's disease (AD). Although studies have shown that combining repetitive transcranial magnetic stimulation (rTMS) with cognitive training (CT) can alleviate AD symptoms, the specific pathophysiological processes involved remain poorly understood. Our goal is to analyze metabolomic changes associated with bilateral cerebellar rTMS plus CT in AD treatment, to identify potential biomarkers of disease progression and therapeutic outcomes, and to validate these findings against a systematic review of existing literature. METHODS: We enrolled 12 individuals with early AD and 12 healthy controls (HC). The AD group received 2 weeks of bilateral cerebellar rTMS combined with CT. We performed ultra-high-performance liquid chromatography-tandem mass spectrometry analysis on serum samples obtained from AD patients (before and after intervention) and HC. The PubMed database was used to conduct a systematic review of AD metabolomics literature, from which differential metabolites were identified and analyzed using pathway enrichment analysis. RESULTS: A total of 510 metabolites were differentially expressed in response to treatment, with 202 consistent with improved clinical status. Fourteen pathways were enriched, including those involved in valine, leucine, and isoleucine biosynthesis, as well as glycine, serine, and threonine metabolism, which are linked to the pathology and treatment of AD. Metabolites such as lysophosphatidylcholine (22:6) and citric acid, increased after treatment and shifted toward healthy control levels, whereas γ-guanidinobutyric acid, proline, decreased after treatment. Systematic review analysis suggested Phenylalanine as a potential biomarker for AD screening at the mild cognitive impairment stage. CONCLUSION: This study's integrative analysis offers preliminary insights into treatment-associated metabolic alterations in AD and identifies candidate metabolites for further investigation as markers of disease status and treatment response. TRIAL REGISTRATION: ChiCTR2200061754.