Are hereditary hemochromatosis mutations involved in Alzheimer disease?

Abstract

Mutations in the class I-like major histocompatibility complex gene called HFE are associated with hereditary hemochromatosis (HHC), a disorder of excessive iron uptake. We screened DNA samples from patients with familial Alzheimer disease (FAD) (n = 26), adults with Down syndrome (DS) (n = 50), and older (n = 41) and younger (n = 52) healthy normal individuals, for two HHC point mutations-C282Y and H63D. Because the apolipoprotein E (ApoE) E4 allele is a risk factor for AD and possibly also for dementia of the AD type in DS, DNA samples were also ApoE genotyped. Chi-squared analyses were interpreted at the 0.05 level of significance without Bonferroni corrections. In the pooled healthy normal individuals, C282Y was negatively associated with ApoE E4, an effect also apparent in individuals with DS but not with FAD. Relative to older normals, ApoE E4 was overrepresented in both males and females with FAD, consistent with ApoE E4 being a risk factor for AD; HFE mutations were overrepresented in males and underrepresented in females with FAD. Strong gender effects on the distribution of HFE mutations were apparent in comparisons among ApoE E4 negative individuals in the FAD and healthy normal groups (P < 0.002). Our findings are consistent with the proposition that among ApoE E4 negative individuals HFE mutations are predisposing to FAD in males but are somewhat protective in females. Further, ApoE E4 effects in our FAD group are strongest in females lacking HFE mutations. Relative to younger normals there was a tendency for ApoE E4 and H63D to be overrepresented in males and underrepresented in females with DS. The possibility that HFE mutations are important new genetic risk factors for AD should be pursued further.

Brain Iron Toxicity: Differential Responses of Astrocytes, Neurons, and Endothelial Cells

“…A significant reduction in transferrin levels is observed in PD and AD and has been suggested as a contributory factor to increases in iron concentrations due to the resulting iron dysregulation [111]. Genetic mutations that impact iron homeostatic mechanisms are associated with certain neurodegenerative disorders [112,113] and may offer an explanation for abnormal iron metabolism in some neurodegenerative disorders. Another theory proposes the possibility of peripheral iron entry into the brain through a disrupted BBB [24].…”

Gender and Iron Genes May Modify Associations Between Brain Iron and Memory in Healthy Aging

“…We also observed that gene variants involved in iron metabolism (hemochromatosis H63D (HFE H63D) and transferrin C2 (TfC2) variants) are associated with higher brain iron levels in healthy older men (Bartzokis et al, 2010). These two gene variants are highly prevalent (affecting approximately 50% of the population), and some studies have shown an association of these variants with higher risk of developing AD (Connor and Lee, 2006;Lehmann et al, 2010;Sampietro et al, 2001;Moalem et al, 2000). We therefore examined memory function in the context of gender and the presence (IRON + ) or absence (IRONÀ) of these iron gene variants.…”

Association between the MHC class I gene HFE polymorphisms and longevity: a study in Sicilian population

“…33 In another study, in patients with familial AD (FAD) C282Y and H63D mutations were over-represented in men and under-represented in women with FAD. 34 Thus, the possibility that HFE mutations are important new genetic risk factors for AD should be pursued further.…”