MODIFYING EFFECTS OF THE HEMOCHROMATOSIS VARIANTS ON CUMULATIVE LEAD EXPOSUREʼS IMPACT ON COGNITIVE DECLINE

Abstract

ISEE-313 Introduction: Lead has long been associated with cognitive impairment. Lead and metals like iron are capable of causing oxidative damage, a purported mechanism of cognitive decline. Variants associated with hereditary hemochromatosis are linked to increased iron and lead absorption. Thus, we investigated whether such variants enhanced lead's detrimental effect on cognitive function. Method: We assessed the modifying effects of the hemochromatosis (HFE) variants on the association between bone lead and change in Mini-Mental State Exam (MMSE) score, among participants in the Normative Aging Study, a Boston-based prospective cohort of men. Tibia and patella leadlevels were measured using K-x-ray fluorescence. Participants were genotyped for both C282Y and H63D variants. We used multiple linear regression to compare the association of lead with change in MMSE score in men of different genotypes, adjusting for age, education, smoking, alcohol intake, English as first language, computer experience and diabetes in all models. In all, 358 men (median age: 67.2) with baseline bone lead measures and genotyping data who had taken the MMSE at least twice were included in the analysis. Results: Mean follow-up period between cognitive tests was 3.2 years. Thirty-five percent of the men had at least one copy of either HFE variants. Tibia and patella lead levels were associated with worse change in MMSE score over time. Although HFE variants themselves did not confer cognitive risk, an interquartile increase in tibia lead level (20 μg/g) was significantly associated with an additional 0.28-point decrement per year in MMSE score among participants with at least one HFE variant (p-value = 0.031), as compared with men without HFE variants. Moreover, there appeared to be a dose effect with greater cognitive decline per unit increase in tibia lead level observed in participants with more copies of variants (test of trend p-value < 0.01). Compared with men with no variant, participants with two copies of HFE variants had MMSE scores which were 0.82 point per year lower for an interquartile increase in tibia lead level (p-value = 0.005). Interestingly, the two HFE variants also showed a synergistic effect on modifying the relation between lead levels and cognitive decline. Participants with either H63D variant or C282Y variant experienced comparable magnitude of cognitive decline associated with tibia lead burden (−0.25 per interquartile increase in tibia lead per year) while participants with both variants (compound heterozygotes) had cognitive decline that was more than twice in magnitude (−1.02 per interquartile increase in tibia lead per year). Effect estimates for patella lead were similar to those observed for tibia lead levels. Discussion: These results suggest that the hemochromatosis variants greatly enhance the effect of lead burden on cognitive decline. Men with more copies of the variants experienced greater cognitive decline per unit increase in bone lead.