Does FOXO3 longevity genotype explain the conflicting data on late‐life hypertension and risk of Alzheimer’s disease?

Abstract

AbstractBackgroundThe association of late‐life hypertension (LHTN) with Alzheimer’s disease (AD) remains controversial. We hypothesize that FOXO3 longevity‐associated genotype modulates the association between LHTN and incident AD.MethodSubjects 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, LHTN at baseline, and diagnosis of incident dementia over 21 years follow‐up. Association of FOXO3 genotype with LHTN and incident all‐cause dementia, vascular dementia (VD) and Alzheimer’s disease was assessed using Cox regression.ResultDuring the 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 LHTN increased VD risk (HR = 1.71, 95%CI = 1.08–2.71, p = 0.022), but not AD risk. We found no significant protective effect of FOXO3 longevity genotype, nor of LHTN, on all‐cause dementia and AD 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 LHTN and FOXO3 longevity genotype on incident AD (ß = –0.52, p = 0.0061). In men with FOXO3 rs2802292 longevity genotype (TG/GG), LHTN showed protection against AD (HR = 0.72; 95% CI = 0.55–0.95, p = 0.021). In men with FOXO3 rs2802292 non‐longevity genotype (TT), LHTN had no protective effect (HR = 1.16; 95% CI = 0.90‐1.51, p = 0.25).DiscussionSince the effect of LHTN on AD incidence differed according to FOXO3 genotype, the overall effect, namely, a weighted average effect of LHTN on AD across different FOXO3 genotypes, would be moving towards the null (i.e., HR = 1). This would explain why most studies have found no significant association between LHTN and AD. One exception is the Ibadan study, in which all participants were African American. African Americans have the highest proportion (94%) of FOXO3 rs2802292 longevity genotype (TG/GG) in all races, and the strongest effect of LHTN in protecting against AD (RR = 0.33).ConclusionThis longitudinal study found that FOXO3 genotype modulates the effect of late‐life hypertension on incident AD, thus explaining the conflicting data on late‐life hypertension and Alzheimer’s disease.