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.