Abstract
Genetic variants of the gene encoding the transcription factor FOXO3 are associated with cell resilience and longevity. Mid-life hypertension is associated with increased risk of vascular dementia and Alzheimer’s disease (AD) at older ages. But the findings for late life hypertension and AD are mixed. The aim of the present study was to determine whether FOXO3 genotype might influence the association between late-life hypertension and incident dementia. Subjects were 2,688 American men of Japanese ancestry free of prevalent dementia at baseline (1991-93, baseline age: 77.0 ± 4.1 years, range 71-93 years) from the Kuakini Honolulu Heart Program. Status was known for FOXO3 rs2802292 genotype, hypertension, and diagnosis of incident dementia to 2012. Association of FOXO3 genotype with late-life hypertension and incident dementia, vascular dementia (VD) and Alzheimer’s disease (AD) was assessed using Cox proportional hazards models. During 21 years of follow-up, 725 men were diagnosed with all-cause dementia, 513 with AD and 104 with VD. A multivariable Cox model, adjusting for age, education, APOE-ε4 and cardiovascular risk factors, showed late-life hypertension increased VD risk only (HR=1.71, 95%CI=1.08-2.71, p =0.022). We found no significant protective effect of FOXO3 longevity genotype on any type of dementia at the population level. However, in a full Cox model adjusting for age, education, APOE-ε4 and other cardiovascular risk factors, there was a significant interaction effect of late-life hypertension and FOXO3 longevity genotypes on incident AD (β= -0.52, p =0.0061). In men with FOXO3 rs2802292 longevity genotypes ( TG / GG ), late-life hypertension showed protection against AD (HR=0.72; 95% CI=0.55-0.95, p =0.021). The non-longevity genotype ( TT ) (HR=1.16; 95% CI=0.90-1.51, p =0.25) had no protective effect. In conclusion, our longitudinal study found that FOXO3 genotype modulates the effect of late-life hypertension on incident AD.
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