Are hereditary hemochromatosis mutations involved in Alzheimer disease?

Mutations in the class I-like major histocompatibility complex gene called HFE are associated with hereditary hemochromatosis (HHC), a disorder of exc essive iron uptake, We screened DNA samples from patients with familial Alz heimer disease (FAD) (n = 26), adults with Down syndrome (DS) (n = 50), and older (n = 41) and younger (n = 52) healthy normal individuals, for two HH C point mutations-C282Y and H63D, Because the apolipoprotein E (ApoE) E4 al lele 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 inte rpreted at the 0.05 level of significance without Bonferroni corrections. I n the pooled healthy normal individuals, C282Y was negatively associated wi th 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 m utations were overrepresented in males and underrepresented in females with FAD. Strong gender effects on the distribution of HFE mutations were appar ent in comparisons among ApoE E4 negative individuals in the FAD and health y normal groups (P < 0.002). Our findings are consistent with the propositi on that among ApoE E4 negative individuals HFE mutations are predisposing t o FAD in males but are somewhat protective in females. Further, ApoE E4 eff ects in our FAD group are strongest in females lacking HFE mutations, Relat ive to younger normals there was a tendency for ApoE E4 and H63D to be over represented in males and underrepresented in females with DS, The possibili ty that HFE mutations are import-ant new genetic risk factors for AD should be pursued further. Am J. Med. Genet. 93:58-66, 2000, (C) 2000 Wiley-Liss, Inc.