Association of Lead Exposure on Cognitive Decline due to Mediation and Interaction with Uric Acid

Abstract

BACKGROUND: Low-level cumulative lead exposure has been associated with cognitive decline in adults. Previous studies suggest that lead increases levels of the antioxidant uric acid and that uric acid may also predict changes in cognitive function. We explored whether uric acid mediated or interacted with lead in the association between lead exposure and cognitive decline.METHODS: From 1991 to 2002, a subset of the Normative Aging Study cohort of community-dwelling men was assessed for cumulative lead exposure in the tibia and patella bones. The Mini-Mental State Examination (MMSE) was administered as a test of global cognition starting in 1992. We conducted formal mediation analysis using the first bone lead measurement, uric acid concurrent with baseline MMSE, and the difference between the second and baseline MMSE scores, adjusted for age at baseline MMSE, education, serum creatinine, smoking status and pack-years, drinking status, and years between the two MMSE tests.RESULTS: 552 men [mean (standard deviation) age: 67.27 (6.52)] took two MMSE tests that were 3.92 (1.80) years apart and had valid bone lead measurements. The total change in MMSE score for an interquartile range (20 µg/g) increase in patella lead was -0.29 (95% confidence interval: -0.49, -0.08) (p=0.007), due mostly to the direct association with lead [-0.25 (-0.44, -0.06) (p=0.01)] when uric acid was set to the mean value; the component due to interaction only was -0.03 (-0.07, 0.004) (p=0.08), due to mediation and interaction was 0.02 (-0.001, 0.05) (p=0.06), and due to mediation only was -0.03 (-0.07, 0.01) (p=0.20). Results with tibia lead were less robust.CONCLUSIONS: Prior studies have indicated significant effects of patella lead on cognitive decline, but accounting for uric acid may be needed to understand the full association between lead and cognitive decline.