Aging Research Center, Department NVS, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
J Alzheimers Dis. 2011;23(3):461-9. doi: 10.3233/JAD-2010-101068.
The FTO gene has been shown to have a small but robust effect on body mass index (BMI) and to increase the risk for diabetes. Both high BMI and diabetes are vascular risk factors that might play a role in the development of Alzheimer's disease (AD) and dementia. Thus, our aim was to explore the impact of FTO on AD and dementia risk. Nine years of follow-up data was gathered from the Kungsholmen project, a prospective population-based study on 1,003 persons without dementia. Cox-regression models were used to assess the relative risks of developing AD and dementia (DSM-III-R criteria) according to FTO genotypes (rs9939609), taking into account APOE, physical inactivity, BMI, diabetes, and cardiovascular disease (CVD). Compared to carriers of the FTO TT-genotype, AA-carriers had a higher risk for AD (RR 1.58, 95% CI: 1.11-2.24) and for dementia (RR 1.48, 95% CI: 1.09-2.02) after adjustment for age, gender, education, and APOE genotype. This effect remained after additional adjustment for physical inactivity, BMI, diabetes, and CVD. An interaction between FTO and APOE was found, with increased risk for dementia for those carrying both FTO AA and APOE ϵ4. Importantly, the effect of the AA-genotype on dementia/AD risk seems to act mostly through the interaction with APOE ϵ4. Our findings suggest that the FTO AA-genotype increases the risk for dementia, and in particular AD, independently of physical inactivity, BMI, diabetes, and CVD measured at baseline. Our results are in line with the recently reported association between FTO and reduced brain volume in cognitively healthy subjects.
FTO 基因已被证明对体重指数（BMI）有微小但显著的影响，并增加患糖尿病的风险。高 BMI 和糖尿病都是血管危险因素，可能在阿尔茨海默病（AD）和痴呆的发展中发挥作用。因此，我们的目的是探讨 FTO 对 AD 和痴呆风险的影响。9 年的随访数据来自 Kungsholmen 项目，这是一项针对 1003 名无痴呆症的前瞻性人群基础研究。使用 Cox 回归模型，根据 FTO 基因型（rs9939609）评估发展为 AD 和痴呆（DSM-III-R 标准）的相对风险，同时考虑 APOE、身体活动不足、BMI、糖尿病和心血管疾病（CVD）。与 FTO TT 基因型携带者相比，AA 基因型携带者发生 AD 的风险更高（RR 1.58，95%CI：1.11-2.24），发生痴呆的风险更高（RR 1.48，95%CI：1.09-2.02），在调整年龄、性别、教育程度和 APOE 基因型后。在进一步调整身体活动不足、BMI、糖尿病和 CVD 后，这种影响仍然存在。发现 FTO 和 APOE 之间存在相互作用，携带 FTO AA 和 APOE ϵ4 的个体痴呆风险增加。重要的是，AA 基因型对痴呆/AD 风险的影响似乎主要通过与 APOE ϵ4 的相互作用发挥作用。我们的研究结果表明，FTO AA 基因型独立于基线时测量的身体活动不足、BMI、糖尿病和 CVD，增加了痴呆的风险，特别是 AD。我们的结果与最近报道的 FTO 与认知健康个体脑容量减少之间的关联一致。
