Abstract
Background/Objectives: Trace metal homeostasis is regulated by nutritional status and is crucial for maintaining redox balance, vascular function, and neuroinflammation. Dysregulation of systemic copper (Cu) metabolism, especially an elevated level of non-ceruloplasmin-bound copper (NCC), has been linked to oxidative stress and early cognitive decline. However, the nutritional and molecular pathways that connect Cu imbalance to mild cognitive impairment (MCI) are not well understood. Methods: We compared the serum Cu and zinc levels of individuals with normal cognition (NC; n = 116) and MCI (n = 184). An exploratory serum proteomic analysis using pooled samples was conducted to investigate patterns related to Cu dysregulation. We identified proteins using pattern correlation analysis and then performed a protein–protein interaction analysis using STRING and functional annotation and biological and Kyoto Encyclopedia of Genes and Genomes pathways. Results: The individuals with MCI had higher NCC levels than those with NC, indicating disrupted Cu metabolism influenced by nutrition and metabolism. The proteomic analysis revealed changes in proteins related to lipid transport, metal balance, and inflammation, including transthyretin, transferrin, apolipoprotein A-I, alpha-1 antitrypsin, antithrombin III, and alpha-2-macroglobulin, which respond to oxidative stress and vascular injury. Conclusions: In this cross-sectional analysis of baseline data, NCC levels were associated with cognitive status and specific circulating proteomic profiles. These findings suggest a potential relationship between copper-related biomarkers and mild cognitive impairment; however, longitudinal studies are required to clarify temporal relationships and potential mechanistic pathways.