Circulating arginine metabolites in Alzheimer's disease and vascular dementia: A systematic review and meta-analysis

Background: Alterations in nitric oxide (NO) synthesis have been reported in Alzheimer's disease and vascular dementia. However, as the measurement of NO in biological samples is analytically challenging, alternative, stable circulatory biomarkers of NO synthesis may be useful to unravel new pathophysiological mechanisms and treatment targets in dementia.Methods: We conducted a systematic review and meta-analysis of the circulating concentrations of arginine metabolites linked to NO synthesis, arginine, citrulline, asymmetric (ADMA) and symmetric (SDMA) dimethylarginine, and ornithine, in Alzheimer's disease and vascular dementia. We searched for relevant studies in PubMed, Scopus, and Web of Science from inception to the 31st of May 2023. The JBI checklist and GRADE were used to assess the risk of bias and the certainty of evidence, respectively.Results: In 14 selected studies, there were no significant between-group differences in arginine and ornithine concentrations. By contrast, compared to controls, patients with dementia had significantly higher ADMA (standard mean difference, SMD=0.62, 95% CI 0.06-1.19, p = 0.029), SDMA (SMD=0.70, 95% CI 0.34-1.35, p<0.001), and citrulline concentrations (SMD=0.50, 95% CI 0.08-0.91, p = 0.018). In subgroup analysis, the effect size was significantly associated with treatment with cholinesterase inhibitors and/or antipsychotics for ADMA, and underlying disorder (Alzheimer's disease), study continent, and analytical method for citrulline.Conclusion: Alterations in ADMA, SDMA, and citrulline, biomarkers of NO synthesis, may be useful to investigate the pathophysiology of different forms of dementia and identify novel therapeutic strategies. (PROSPERO registration number: CRD42023439528)