Urine Exposome–Metabolome Network Analysis Identifies Differential Chemical Connectivity Associated with Mild Cognitive Impairment

Mild cognitive impairment (MCI) represents a transitional neurocognitive state vulnerable to environmental modulation, yet the exposomic underpinnings remain poorly characterized. In this study, we performed integrated urinary exposome and metabolome profiling in 30 MCI patients and 30 matched controls using a broad-spectrum targeted LC-MS/MS platform encompassing 239 xenobiotics and 688 endogenous metabolites. To characterize systemic environmental-metabolic interactions, exposome-metabolome (E × M) correlation networks were constructed through bootstrap-resampled Spearman analysis. Although total xenobiotic burdens were comparable between groups, MCI individuals exhibited significantly elevated chemical richness and E × M network hyperconnectivity, suggesting heightened metabolic reactivity to environmental stimuli. A core differential E × M network was delineated, identifying 1-hydroxypyrene, perfluorooctanoic acid, and NEtFOSAA as central environmental hubs, and acetylcholine, guanine, and l-methionine as key metabolic nodes associated with MCI status and AD8 cognitive scores. These molecules converge on oxidative stress, neuroinflammation, cholinergic dysregulation, and epigenetic perturbation pathways. Our findings underscore the pathophysiological relevance of chemical-metabolic crosstalk in early cognitive decline and advocate for exposome-informed precision neurology frameworks.