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Blood micronutrients modified associations between blood heavy metals and cognitive decline in a nationally representative cross-sectional study.

Chunliang Liu,Tianchen Sheng,Hao Fan,Jianjun Zhang

Published 2026 in American Journal of Clinical Nutrition

ABSTRACT

BACKGROUND Although previous studies showed that heavy metal exposure and antioxidant micronutrient insufficiency were associated with cognitive impairment, their combined influence on cognitive function remain unclear. OBJECTIVES This study investigated the associations of blood lead, cadmium, selenium, erythrocyte folate, and serum 25(OH)D with cognitive performance and the interactions between heavy metals and micronutrients considered in a U.S. cross-sectional study. METHODS Data from 2,858 participants aged ≥60 years in the National Health and Nutrition Examination Survey 2011-2014 were analyzed. Multivariable linear and logistic regression models were constructed to evaluate the main effects of heavy metals and micronutrients and their additive and multiplicative interactions on cognitive function. RESULTS After adjustment for confounders, blood lead [β (95% CI): -1.67 (-3.32, -0.03)] and cadmium [-2.02 (-3.19, -0.85)] were inversely and serum 25(OH)D [2.23 (0.88, 3.59)] was positively associated with the Digit Symbol Substitution Test (DSST) score (a higher score indicating better cognitive function). Significant additive and multiplicative interactions between blood lead and erythrocyte folate, between blood lead and serum 25(OH)D, and between blood cadmium and erythrocyte folate in relation to low DSST score were detected. Compared with individuals in the first quartile of a weighted composite score of risk factors (defined as ≥median for 2 metals or <median for 3 micronutrients), those in the quartiles 2 through 4 demonstrated a progressively higher risk of low cognitive function assessed by the DSST score [OR (95% CI): 1.58 (0.95, 2.61), 2.00 (1.18, 3.39), and 2.45 (1.44, 4.17), respectively; p-trend: 0.00083]. CONCLUSIONS This study revealed that the neurodegenerative influence of heavy metals is more pronounced in individuals with lower micronutrient status. If the results of the present study are confirmed by future studies, reducing heavy metal exposure and improving micronutrient status may offer a novel and practical strategy for preventing cognitive decline and dementia.

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