Age stratification corrects bias in estimated hazard of APOE genotype for Alzheimer's disease.
Age stratification corrects bias in estimated hazard of APOE genotype for Alzheimer's disease.
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DOI：
10.1016/j.trci.2018.09.006
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Caselli RJ
中科院分区：
文献类型：
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作者：
Liu L;Caselli RJ
载脂蛋白E (APOE) e4等位基因是迟发性阿尔茨海默病的主要遗传危险因素。然而，它与另外两个典型的风险因素——年龄和性别——的相互作用尚不清楚。先前的研究报告了其在男性和女性中的差异效应，其与65岁之前的年轻发病AD的关联，以及其在遗传混合人群中的重要性等方面的相互矛盾的结果。在这些研究中，假设e4等位基因的危害在衰老过程中是恒定的。然而，这一假设尚未经过检验，违反这一假设可能会导致显著的偏差，并导致这种差异的发现。在4727名受试者的前瞻性队列中，我们对e4等位基因与AD发病年龄的关系进行了Cox回归分析。然后，我们对得到的模型进行诊断，并测试e4等位基因的危害在衰老过程中是否违反了比例假设。我们研究了合并年龄分层和时间相关系数是否可以恢复比例。然后，我们在四个独立的队列中验证了我们的发现。e4等位基因对AD的危害不成比例。男性在80岁左右，女性在75岁左右，记忆力逐渐下降。通过将受试者分为年轻组和老年组，我们发现e4等位基因在多个独立队列中的影响更加一致。我们还发现，e4等位基因是65岁之前发病的年轻AD的重要危险因素。研究队列的年龄构成会显著影响APOE基因型的估计效果。阿尔茨海默病的研究应考虑受试者中隐藏的年龄结构，并在实验设计和数据分析中常规采用适当的年龄和性别分层策略或非参数建模。最后，我们认为e4等位基因不仅是迟发性AD的危险因素，也是年轻发病AD的危险因素。
The apolipoprotein E (APOE) e4 allele is a major genetic risk factor of late-onset Alzheimer's disease. However, its interaction with two other canonical risk factors, age and sex, is not clear. Previous studies have reported conflicting results on its differential effects in men and women, its association with young-onset AD before the age of 65 years, and its significance in genetic admixture populations. In these studies, the hazard of the e4 allele was assumed to be constant during aging. However, this hypothesis has not been tested and its violation may lead to significant biases and contribute to such discrepant findings. In a prospective cohort of 4727 subjects, we performed Cox regression analysis of the association of the e4 allele with AD age of onset. We then performed diagnostics on the resulting model and tested if the hazard of the e4 allele violated the assumption of proportionality during aging. We examined whether incorporating age stratifications and time-dependent coefficients could restore the proportionality. We then validated our findings in four independent cohorts. Hazard of the e4 allele for AD was nonproportional. It took a stepwise decline around the age of 80 years for men and around the age of 75 years for women. By stratifying subjects into a younger group and an older group, we detected more consistent effects of the e4 allele across multiple independent cohorts. We also found that the e4 allele was a significant risk factor for young-onset AD with age of onset before 65 years. Age compositions of study cohorts can significantly bias the estimated effect of the APOE genotype. Studies of AD should consider hidden age structures among subjects and routinely employ appropriate age and sex stratification strategies or nonparametric modeling in experimental designs and data analysis. Finally, we argue that the e4 allele is a risk factor not only for late-onset AD but also for young-onset AD.