Symptom onset in autosomal dominant Alzheimer disease A systematic review and meta-analysis
Symptom onset in autosomal dominant Alzheimer disease A systematic review and meta-analysis
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DOI：
10.1212/wnl.0000000000000596
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发表时间：
2014-07-15
期刊：
影响因子：
9.9
通讯作者：
Bateman, Randall J.
中科院分区：
文献类型：
--
作者：
Ryman, Davis C.;Acosta-Baena, Natalia;Bateman, Randall J.
目的：目的探讨常染色体显性遗传阿尔茨海默病（ADAD）发病年龄和病程的影响因素，并建立ADAD发病的循证预测标准。我们从387个ADAD家系中收集了关于症状发作和死亡年龄的个体水平数据，这些数据来自137篇同行评议的出版物、显性遗传阿尔茨海默病网络（DIAN）数据库，以及哥伦比亚血统（PSEN 1 E280 A）和伏尔加血统（PSEN 2 N141 I）的2个大家族。我们的综合数据集包括3，275名个体，其中1，307名受ADAD影响，症状发作时年龄已知。我们评估了影响发病年龄的几个因素的相对贡献，包括父母发病年龄，突变类型和家族的发病年龄，以及APOE基因型和性别。我们还使用DIAN研究中纵向随访的183例ADAD突变携带者的症状发作数据进行了生存分析。我们报告了174个ADAD突变的发病年龄和病程的汇总统计，发现了强而高度显著的（p < 10（-16），r（2）> 0.38）个体发病年龄与基于父母发病年龄的预测值之间的相关性以及突变类型和家族的平均发病年龄，结论：ADAD患者发病年龄的显著差异可以用家族史和突变类型来解释，为临床研究中利用这些数据来估计发病提供了经验支持。
Objective: To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD.Methods: We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study.Results: We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p < 10(-16), r(2) > 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex.Conclusions: Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research.