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Risk Factors for Development of Dementia in a Unique Six-Year Cohort Study. I. An Exploratory, Pilot Study of Involvement of the E4 Allele of Apolipoprotein E, Mutations of the Hemochromatosis-HFE Gene, Type 2 Diabetes, and Stroke

Article type: Research Article

Authors: Percy, Mairea; * | Somerville, Martin J.b | Hicks, Markb; c | Colelli, Teresaa | Wright, Emilya | Kitaygorodsky, Juliaa | Jiang, Amya | Ho, Valeriea | Parpia, Alyssaa | Wong, Michael K.a | Garcia, Angelesd; *

Affiliations: [a] Departments of Physiology and Obstetrics & Gynaecology, University of Toronto, Toronto ON, Canada, Surrey Place Centre, Toronto ON, Canada | [b] Department of Medical Genetics, University of Alberta, Edmonton AB, Canada | [c] Present Address: Alberta Health Services, Edmonton AB, Canada | [d] Division of Geriatrics, Department of Medicine, Queen's University, Kingston ON, Canada

Correspondence: [*] Correspondence to: Maire Percy, Ph.D., Surrey Place Centre, Room 216, 2 Surrey Place, Toronto, Ontario M5S 2C2, Canada. Tel.: +1 416 925 2169/Ext. 2353 (work); Fax: +1 416 923 8476; E-mail: [email protected], Dr. Angeles Garcia, Queens University, St. Mary's of the Lake Hospital, Kingston, PO Box 3600, 340 Union Street, Kingston, Ontario K7L 5A2, Canada. Tel.: +1 613 544 5220; Fax: +1 613 544 4017; E-mail: [email protected].

Keywords: Alzheimer's disease, apolipoprotein E, C282Y, cohort study, dementia, HFE mutations, H63D, hemochromatosis, iron, mild cognitive impairment, risk factors, stroke, type 2 diabetes mellitus

DOI: 10.3233/JAD-131409

Journal: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 907-922, 2014

Accepted 19 August 2013
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Published: 10 December 2013
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Abstract

Risk factors for dementia development are not well-defined. We evaluated several factors alone and in combination in a unique cohort of Caucasian volunteers over an approximately 6-year observation window using a nested case/control design. Factors included: apolipoprotein E (ApoE) gene variants (the E4 allele is the strongest confirmed genetic predisposing factor for Alzheimer's disease), the hemochromatosis-HFE gene mutations (H63D and C282Y), diabetes, and stroke. At study entry, subjects were ≥65 years of age (M ± SD = 73.0 ± 4.9), had an MMSE score ≥24, and no evidence of cerebrovascular disease or current depression. Genotyping was completed on 163 available DNA samples from three different groups at the study end: those who still had normal cognitive function; those who had developed dementia; and those with Mild Cognitive Impairment (MCI). Analyses were interpreted at the 95% confidence level without Bonferroni corrections. In the subgroup with dementia, all cases of diabetes were type 2 and present at study entry, whereas all strokes occurred during the study. The results highlight apparently synergistic interactions between genetic and medical risk factors for dementia development, gender differences in risk factors, and involvement of HFE mutations. Having E4 (i.e., either of E3/4 or E4/4), C282Y, H63D, diabetes, or stroke alone did not attain significance. Significant predisposing factors with post-hoc power ≥80% were: E4 homozygosity (E4/4)males+females, odds ratio (OR) = 56.0); E4+diabetes (males+females, OR = 13.7; E4+H63D+diabetes (females, OR = 52.0); E4+stroke (males, OR = 46.5). The importance of preventing diabetes and stroke to ward off dementia and the possible role of iron dysmetabolism in dementia are discussed.

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