Incidence of Alzheimer’s Disease in Men with Late-Life Hypertension Is Ameliorated by FOXO3 Longevity Genotype

Abstract

Background: It is well established that mid-life hypertension increases risk of dementia, whereas the association of late-life hypertension with dementia is unclear. Objective: To determine whether FOXO3 longevity-associated genotype influences the association between late-life hypertension and incident dementia. Methods: Subjects were 2,688 American men of Japanese ancestry (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 (VaD) and Alzheimer’s disease (AD) was assessed using Cox proportional hazards models. Results: During 21 years of follow-up, 725 men were diagnosed with all-cause dementia, 513 with AD, and 104 with VaD. A multivariable Cox model, adjusting for age, education, APOE ɛ4, and cardiovascular risk factors, showed late-life hypertension increased VaD 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 ɛ4, and other cardiovascular risk factors, there was a significant interaction effect of late-life hypertension and FOXO3 longevity genotype on incident AD (β= –0.52, p = 0.0061). In men with FOXO3 rs2802292 longevity genotype (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. Conclusion: This longitudinal study found late-life hypertension was associated with lower incident AD in subjects with FOXO3 genotype.