Modifying Effects of the HFE Polymorphisms on the Association between Lead Burden and Cognitive Decline

In the United States the population of persons age 65 years and older is projected to increase 2-fold to 75 million in the next 30 years, and a concomitant upsurge in the number of individuals with dementia is expected (U.S. Census Bureau 2000a, 2000b). Cognitive decline, a risk factor for dementia, may be a transition stage spanning normal cognition and onset of diseases associated with dementia (Bischkopf et al. 2002; Burns and Zaudig 2002; Pratico et al. 2002). Lead has long been recognized as a neuro-toxicant; the associations between lead and cognitive impairment among workers in lead-related industries and poorer cognitive development in children have been well reproduced (Barth et al. 2002; Bleecker et al. 1997; Lanphear et al. 2000). The few studies that have been conducted among low-level lead-exposed older adults have generally reported inverse associations between lead burden and cognitive function (Muldoon et al. 1996; Nordberg et al. 2000; Payton et al. 1998; Weisskopf et al. 2004; Wright et al. 2003). With half-life estimates ranging from 5 to 20 years for cortical bone, and more than1 year for trabecular bone (Hu et al. 1998; Kim et al. 1997), lead levels in bone may better reflect long-term body burden of lead than blood lead, which has a half-life of approximately 30 days (Hu 2001). In addition, bone lead measures correlate well with measures of cumulative external lead levels and integrated blood lead levels, two commonly used indices of cumulative lead exposure (Bleecker et al. 1997). Iron metabolism may play a critical role in neurodegenerative processes (Lee et al. 2006; Todorich and Connor 2004). Although iron is vital for cellular processes, plasma iron which is not bound to transferrin may be toxic. This nontransferrin-bound iron represents the portion of body iron likely to cause cellular oxidative damage, a purported mechanism in the pathogenesis of neurodegenerative diseases, and serve as a catalyst in the neuronal production of free radicals (Eaton and Qian 2002; Samson and Nelson 2000). Two variants in the hemochromatosis (HFE) gene, C282Y and H63D, are commonly found in the U.S.population, especially among whites, and are associated with hereditary hemochromatosis, a disease of iron overload. Several recent studies have reported an association between these HFE polymorphisms and neurodegenerative diseases such as Alzheimer disease (Berlin et al. 2004; Moalem et al. 2000; Sampietro et al. 2001). Furthermore, carriers of these polymorphisms who do not have clinical signs of iron overload are observed to have higher levels of nontransferrin-bound iron in addition to body iron measures higher than wild-types (Adams et al. 2005; Beutler et al. 2003; Datz et al. 1998; de Valk et al. 2000; Garry et al. 1997). These studies have led to a growing interest in the interaction of iron and lead metabolism in the process of neurodegeneration. As HFE variant alleles are associated with neurodegenerative processes similar to those seen in lead toxicity, and the presence of iron enhances the oxidative effects of lead (Adonaylo and Oteiza 1999), HFE variant alleles may magnify the neurologic damage caused by lead. Therefore, we examined the modifying effect of the HFE alleles on the association between body lead burden and change in performance on the Mini-Mental State Examination (MMSE), a test of global cognitive function, in a cohort of older, community-dwelling men.