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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]