Liu Li, Caselli Richard J
Department of Biomedical Informatics, Arizona State University, Scottsdale, AZ, USA.
Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ, USA.
Alzheimers Dement (N Y). 2018 Oct 30;4:602-608. doi: 10.1016/j.trci.2018.09.006. eCollection 2018.
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.
载脂蛋白E（APOE）ε4等位基因是晚发性阿尔茨海默病的主要遗传风险因素。然而，其与另外两个典型风险因素——年龄和性别之间的相互作用尚不清楚。此前的研究报告了关于其在男性和女性中的差异效应、与65岁之前早发性阿尔茨海默病的关联以及在遗传混合人群中的意义的相互矛盾的结果。在这些研究中，ε4等位基因的风险在衰老过程中被假定为恒定的。然而，这一假设尚未得到验证，其违背可能导致显著偏差并造成此类不一致的研究结果。
在一个由4727名受试者组成的前瞻性队列中，我们对ε4等位基因与阿尔茨海默病发病年龄的关联进行了Cox回归分析。然后我们对所得模型进行诊断，并测试ε4等位基因的风险在衰老过程中是否违背了比例性假设。我们研究了纳入年龄分层和时间依赖系数是否能恢复比例性。然后我们在四个独立队列中验证了我们的研究结果。
ε4等位基因导致阿尔茨海默病的风险是非比例性的。男性在80岁左右、女性在75岁左右出现逐步下降。通过将受试者分为较年轻组和较年长组，我们在多个独立队列中检测到ε4等位基因更一致的效应。我们还发现，ε4等位基因是65岁之前早发性阿尔茨海默病的一个显著风险因素。
研究队列的年龄构成会显著影响APOE基因型估计效应的偏差。阿尔茨海默病的研究应考虑受试者之间隐藏的年龄结构，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ε4等位基因不仅是晚发性阿尔茨海默病的风险因素，也是早发性阿尔茨海默病的风险因素。
