Metallomics analysis of metal exposure and cognitive function in older adults: A combined epidemiological and bioinformatics study.

Dementia is a significant cause of elderly disability and Alzheimer's disease (AD) is the most prevalent form of dementia. As an early stage of AD, the mechanism related to mild cognitive impairment (MCI) and heavy metals is still unclear. This study utilized a cross-sectional design and enrolled 514 older adults in Bejing, China. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) and fourteen blood metals were measured by inductively coupled plasma mass spectrometry (ICP-MS). In the adjusted single-metal models, we observed that copper [Cu, β (95% CI): 3.73 (-6.42, -1.03)] and lead [Pb, β (95% CI): 0.79 (-1.26, -0.32)] demonstrated negative associations with cognitive function, while selenium [Se, β (95% CI): 2.97 (1.23, 4.70)] was beneficial to cognition. Our findings were robust in secondary analysis using multi-metal models, which included generalized linear models (GLM), Bayesian kernel machine regression (BKMR), and quantile g-computation (qgcomp). Moreover, the toxic metal mixture (Cu and Pb) exhibited a significant negative association with MMSE scores and the inclusion of Se in the metal mixture attenuated the neurotoxicity of Cu-Pb mixture. The in silico analysis was used to examine the potential molecular mechanisms (genes, biological processes, pathways, and illnesses) of interaction among metal mixtures. We identified 20 cognition-related genes that are associated with both Cu-Pb and Se. Among these genes, eight (APOE, APP, BAX, BDNF, CASP3, HMOX1, TF, and TPP1) exhibited opposite effects on protein activity, mRNA expression, or protein expression in response to Se and Cu/Pb exposure, which could be the key genes accounting for the anti-neurotoxic effects of Se. Our findings support that Se can attenuate the neurotoxicity of exposure to single Cu or Pb, and Cu-Pb mixture. More research is needed to confirm our findings and gain knowledge about the molecular mechanisms of combined metal exposure on cognitive function.