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

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.

No Genetic Overlap Between Circulating Iron Levels and Alzheimer’s Disease

“…We did not replicate the previous finding of an effect of HFE SNPs on risk of AD and an epistatic interaction for risk with APOE ε4 genotype, but we cannot yet rule out an association of HFE SNPs with AD age of onset or phenotypic interactions [25,27,28].…”

“…Several studies previously reported an increased frequency of the HFE H63D (rs1799945) mutation in AD patients [25], but these findings have not been replicated in the largest AD GWAS meta-analysis [26]. There is evidence of interaction effects, which would not be apparent in GWAS meta-analyses, involving H63D and APOE ε4 alleles where the combination appears to affect age of onset and, to a lesser extent, risk [27][28][29].…”

Interaction of Apolipoprotein E Genotypes, Lifestyle Factors and Future Risk of Dementia-Related Mortality: The Cohort of Norway (CONOR)

“…Whether this increased risk is augmented by ApoE ε4 carrier status for general dementia or only restricted to risk of AD is unresolved [4,8]. Several studies investigating the interaction between ApoE and lifestyle risk factors regarding dementia risk have been hampered by a low statistical power by including too few subjects with later dementia; typically, the studies have 30-130 cases [4,9,10,11,12,13,14]. For example, the Finnish CAIDE study investigated ApoE ε4 and lifestyle-related factors, such as physical activity [12], alcohol use [13] and fat intake [14], and risk of dementia, but with 50-120 cases included.…”

Assessment of Possible Association Between Antioxidant Levels and Apoe Gene Polymorphism in Demented Saudi Population

“…For example, Alzheimer's disease has more than 200 genes that might be involved in its pathogenesis (Cacabelos, 2008). In general, only apolipoprotein E4 gene is consistent between studies as the strongest genetic risk factor linked tomost common dementia subtype in various populations (Harold et al, 2009;Percy et al, 2014;Alzheimer's Association, 2017).…”