Department of Neurology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA.
JAMA. 2010 Jan 13;303(2):150-8. doi: 10.1001/jama.2009.1988.
Polymorphisms in the cholesteryl ester transfer protein (CETP) gene have been associated with exceptional longevity and lower cardiovascular risk, but associations with memory decline and dementia risk are unclear.
To test the hypothesis that a single-nucleotide polymorphism (SNP) at CETP codon 405 (isoleucine to valine V405; SNP rs5882) is associated with a lower rate of memory decline and lower risk of incident dementia, including Alzheimer disease (AD).
DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study comprising 608 community-dwelling adults without dementia aged 70 years or older from the Einstein Aging Study with CETP genotype available. Fifteen participants with prevalent dementia were excluded, and 70 without follow-up--63 lost to follow-up and 7 new to the study--were excluded from the Cox proportional hazards model, which included 523 participants in the analysis. Standardized neuropsychological and neurological measures were administered annually from 1994-2009. Linear mixed-effects models adjusted for sex, education, race, medical comorbidities, and apolipoprotein (APOE) epsilon4 examined associations of V405 genotype with longitudinal performance on cognitive tests of episodic memory (Free and Cued Selective Reminding Test [FCSRT], possible scores of 0-48), attention (Digit Span), and psychomotor speed (Digit Symbol Substitution). The V405 genotype was the main predictor of incident dementia or AD in similarly adjusted Cox proportional hazards models with age as the time scale.
Memory decline and incident dementia.
Valine allele frequency was 43.5%. A total of 40 cases of incident dementia occurred during follow-up (mean [(SD], 4.3 [3.1] years). Compared with isoleucine homozygotes, valine homozygotes had significantly slower memory decline on the FCSRT (0.43 points per year of age for isoleucine; 95% confidence interval [CI], -0.58 to -0.29 vs 0.21 points per year of age for valine; 95% CI, -0.39 to -0.04; difference in linear age slope, 0.22; 95% CI, 0.02 to 0.41; P = .03) and no significant differences on the Digit Span or Digit Symbol Substitution tests. Valine homozygotes also had lower risk of dementia (hazard ratio, 0.28; 95% CI, 0.10-0.85; P = .02) and AD (hazard ratio, 0.31; 95% CI, 0.10-0.95; P = .04).
This preliminary report suggests that CETP V405 valine homozygosity is associated with slower memory decline and lower incident dementia and AD risk.
胆固醇酯转移蛋白（CETP）基因中的多态性与长寿和较低的心血管风险有关，但与记忆衰退和痴呆风险的关联尚不清楚。
测试胆固醇酯转移蛋白密码子 405 处的单核苷酸多态性（SNP）（异亮氨酸到缬氨酸 V405；SNP rs5882）与记忆衰退速度较慢和痴呆事件风险较低（包括阿尔茨海默病[AD]）相关的假设。
设计、地点和参与者：这是一项包括来自爱因斯坦衰老研究的 608 名年龄在 70 岁或以上、无痴呆的社区居民的前瞻性队列研究，且可获得 CETP 基因型。排除了 15 名有明显痴呆的参与者，排除了 70 名无随访的参与者（63 名失访，7 名新入组），从 Cox 比例风险模型中排除了这 70 名参与者，该模型包括 523 名参与者。1994-2009 年每年进行标准化神经心理学和神经学评估。线性混合效应模型调整了性别、教育、种族、医学合并症和载脂蛋白（APOE）ε4，以研究 V405 基因型与认知测试（自由和线索选择性回忆测试[FCSRT]，可能得分为 0-48）、注意力（数字跨度）和精神运动速度（数字符号替代测试）的纵向表现之间的关联。在年龄作为时间尺度的类似调整的 Cox 比例风险模型中，V405 基因型是痴呆或 AD 事件的主要预测因子。
记忆衰退和痴呆事件。
缬氨酸等位基因频率为 43.5%。在随访期间共发生了 40 例痴呆事件（平均[SD]，4.3[3.1]年）。与异亮氨酸纯合子相比，缬氨酸纯合子的 FCSRT 记忆衰退速度较慢（异亮氨酸每年 0.43 分；95%置信区间[CI]，-0.58 至 -0.29 与缬氨酸每年 0.21 分；95%CI，-0.39 至 -0.04；线性年龄斜率差异，0.22；95%CI，0.02 至 0.41；P=0.03），但在数字跨度或数字符号替代测试中无显著差异。缬氨酸纯合子痴呆（危险比，0.28；95%CI，0.10-0.85；P=0.02）和 AD（危险比，0.31；95%CI，0.10-0.95；P=0.04）的风险也较低。
本初步报告表明，CETP V405 缬氨酸纯合子与记忆衰退速度较慢、痴呆和 AD 风险较低相关。
