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Iron overload may contribute to the risk of Alzheimer's disease (AD). In the Epistasis Project, with 1757 cases of AD and 6295 controls, we studied 4 variants in 2 genes of iron metabolism: hemochromatosis (HFE) C282Y and H63D, and transferrin (TF) C2 and -2G/A. We replicated the reported interaction between HFE 282Y and TF C2 in the risk of AD: synergy factor, 1.75 (95% confidence interval, 1.1-2.8, p = 0.02) in Northern Europeans. The synergy factor was 3.1 (1.4-6.9; 0.007) in subjects with the APOEε4 allele. We found another interaction, between HFE 63HH and TF -2AA, markedly modified by age. Both interactions were found mainly or only in Northern Europeans. The interaction between HFE 282Y and TF C2 has now been replicated twice, in altogether 2313 cases of AD and 7065 controls, and has also been associated with increased iron load. We therefore suggest that iron overload may be a causative factor in the development of AD. Treatment for iron overload might thus be protective in some cases.

Original publication

DOI

10.1016/j.neurobiolaging.2010.07.018

Type

Journal

Neurobiol Aging

Publication Date

01/2012

Volume

33

Pages

202.e1 - 202.13

Keywords

Aged, Aged, 80 and over, Aging, Alzheimer Disease, Apolipoprotein E4, Epistasis, Genetic, Female, Hemochromatosis Protein, Histocompatibility Antigens Class I, Humans, Iron Chelating Agents, Iron Overload, Male, Membrane Proteins, Oxidative Stress, Risk, Transferrin