Transferrin and HFE genes interact in Alzheimer's disease risk: The Epistasis Project

Donald J. Lehmann, Maaike Schuur, Donald R. Warden, Naomi Hammond, Olivia Belbin, Heike Kölsch, Michael G. Lehmann, Gordon K. Wilcock, Kristelle Brown, Patrick G. Kehoe, Chris M. Morris, Rachel Barker, Eliecer Coto, Victoria Alvarez, Panos Deloukas, Ignacio Mateo, Rhian Gwilliam, Onofre Combarros, Alejandro Arias-Vásquez, Yurii S. AulchenkoM. Arfan Ikram, Monique M. Breteler, Cornelia M. van Duijn, Abderrahim Oulhaj, Reinhard Heun, Mario Cortina-Borja, Kevin Morgan, Kathryn Robson, A. David Smith

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)


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 languageEnglish
Pages (from-to)202.e1-202.e13
JournalNeurobiology of Aging
Issue number1
Publication statusPublished - Jan 2012
Externally publishedYes


  • Apolipoprotein E ε4
  • Glycosylation
  • Iron chelation
  • Microglia
  • Mild cognitive impairment
  • Neurodegeneration
  • Onset age
  • Transferrin saturation

ASJC Scopus subject areas

  • General Neuroscience
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology


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