Involvement of ApoE E4 and H63D in Sporadic Alzheimer's Disease in a Folate-Supplemented Ontario Population

Article type: Research Article

Authors: Percy, Maire^{a; *} | Moalem, Sharon^{a; b} | Garcia, Angeles^c | Somerville, Martin J.^d | Hicks, Mark^e | Andrews, David^e | Azad, Azar^f | Schwarz, Peter^a | Zavareh, Reza Beheshti^a | Birkan, Rivka^a | Choo, Clara^a | Chow, Vinca^a | Dhaliwal, Sandeep^a | Duda, Victoria^a | Kupferschmidt, Anthony L.^{c; g} | Lam, Kyla^a | Lightman, Deborah^a | Machalek, Karolina^a | Mar, Wanna^h | Nguyen, Frank^a | Rytwinski, Piotr J.^{a; 1} | Svara, Erin^c | Tran, Maithy^a | Yeung, Lisa^a | Zanibbi, Katherine^c | Zener, Rebecca^a | Ziraldo, Melissa^h | Freedman, Morrisⁱ

Affiliations: [a] Surrey Place Centre and Departments of Physiology and Obstetrics & Gynaecology, University of Toronto, Toronto, ON, Canada | [b] Mount Sinai School of Medicine, New York, NY, USA | [c] Department of Medicine, Queen's University, Kingston, ON, Canada | [d] Department of Medical Genetics and Pediatrics, University of Alberta, Edmonton, AB, Canada | [e] Department of Statistics, University of Toronto, ON, Canada | [f] Department of Laboratory Medicine and Pathobiology, Mount Sinai Hospital, Toronto, ON, Canada | [g] Department of Gerontology, Simon Fraser University, Vancouver, BC, Canada | [h] Behavioural Neurology Program, Division of Neurology, and Rotman Research Institute, Baycrest Centre for Geriatric Care, Toronto, ON, Canada | [i] Department of Medicine, Division of Neurology, Mount Sinai Hospital, University Health Network and University of Toronto, ON, Canada

Correspondence: [*] Corresponding author: Maire E. Percy, Ph.D., Neurogenetics Laboratory, Surrey Place Centre, 2 Surrey Place, Toronto, Ontario M5S 2C2, Canada. Tel.: +1 416 925 2169 ext. 2353; Fax: +1 416 923 8476; E-mail: maire.percy@utoronto.ca.

Note: [1] Deceased; this paper is dedicated to his memory.

Note: [] Communicated by James Connor.

Abstract: Dysregulation of iron homeostasis is implicated in Alzheimer's disease (AD). In this pilot study, common variants of the apolipoprotein E (APOE) and HFE genes resulting in the iron overload disorder of hereditary hemochromatosis (C282Y, H63D and S65C) were evaluated as factors in sporadic AD in an Ontario sample in which folic acid fortification has been mandatory since 1998. Laboratory studies also were done to search for genetic effects on blood markers of iron status, red cell folates and serum B12. Participants included 58 healthy volunteers (25 males, 33 females) and 54 patients with probable AD (20 males, 34 females). Statistical analyses were interpreted at the 95% confidence level. Contingency table and odds ratio analyses supported the hypothesis that in females of the given age range, E4 significantly predisposed to AD in the presence but not absence of H63D. In males, E4 significantly predisposed to AD in the absence of H63D, and H63D in the absence of E4 appeared protective against AD. Among E4+ AD patients, H63D was associated with significant lowering of red cell folate concentration, possibly as the result of excessive oxidative stress. However, folate levels in the lowest population quartile did not affect the risk of AD. A model is presented to explain the experimental findings.

Keywords: APOE, folate, HFE, iron status, sporadic Alzheimer's disease

DOI: 10.3233/JAD-2008-14107

Journal: Journal of Alzheimer's Disease, vol. 14, no. 1, pp. 69-84, 2008