Associations between Metals, Serum Folate, and Cognitive Function in the Elderly: Mixture and Mediation Analyses

Exposure to metals may potentially impact cognitive health in the elderly; however, the evidence remains ambiguous. The specific role of serum folate in this relationship is also unclear. We aimed to evaluate the individual and joint impact of metals on cognition in the elderly from the United States and explore the potential mediating effect of serum folate. Data from the NHANES 2011-2014 were used, with inductively coupled plasma mass spectrometry (ICP-MS) employed to measure blood metal concentrations. Cognitive function was assessed using tests for immediate, delayed, and working memory: Immediate Recall test (IRT), the Delayed Recall test (DRT), the Animal Fluency test (AFT), and the Digit Symbol Substitution test (DSST). Generalized linear regression models (GLMs), Bayesian kernel machine regression model (BKMR), and quantile g-computation (QG-C) models were used to assess associations between metals (lead, cadmium, mercury, selenium, manganese) and cognition, with mediation analyses examining serum folate's involvement in metal effects. This study included 2002 participants aged ≥60. GLMs revealed the negative association between cadmium and the z-scores of IRT (β: -0.17,95% CI: -0.30, -0.04) and DSST (β: -0.15,95% CI: -0.27, -0.04), with negative effects also observed in the BKMR and QG-C models. Selenium displayed significantly positive association with cognition across various statistical models, including GLMs, QG-C, and BKMR. Serum folate played a mediating role in the effects of cadmium and selenium exposure on DSST z-scores, with a proportion of mediation of 17% and 10%, respectively. Our study assessed the impact of metal mixtures on cognition in the elderly population, finding that high selenium level was strongly associated with better cognitive performance, while cadmium was associated with lower cognitive function scores. Serum folate might partially mediate the association between cadmium, selenium, and DSST z-scores.