Salivary metabolomics for early detection of vascular contributions to cognitive impairment and dementia: Exploring microbiome dysbiosis and sex differences

Background Vascular factors contribute to dementia in approximately 20 million individuals, notably in vascular contributions to cognitive impairment and dementia (VCI). However, the lack of specific molecular biomarkers to differentiate VCI from normal aging and Alzheimer's disease (AD) impedes early diagnosis and treatment. Objective To date the use of saliva for VCI diagnosis has not been previously reported. In this small proof-of-concept study, we aim to explore the feasibility of screening novel salivary diagnostic biomarkers for VCI. Methods Using both proton nuclear magnetic resonance ( 1 H NMR) spectroscopy and liquid chromatography coupled with mass spectrometry (LC-MS) we biochemically profiled saliva samples collected from individuals with VCI (n = 26) and compared them with cognitively healthy controls (n = 37). Results Of the 167 salivary metabolites 56 of them are found to be at significantly different concentrations in the saliva of individuals with VCI as compared to controls. Subsequently, we developed predictive models capable of distinguishing VCI from controls with 0.92 accuracy. Moreover, sex-stratified analysis revealed the perturbation of different metabolic pathways in the saliva of individuals with VCI. Conclusions This study underscores the promising role of salivary metabolomics as a non-invasive tool for the early detection of VCI. Our findings suggest that oral microbiome dysbiosis may contribute to VCI pathogenesis, offering novel mechanistic insights. Given the accessibility of saliva, further validation of these robust salivary biomarkers could facilitate scalable, cost-effective screening for VCI, aiding in timely intervention strategies.