DEMOGRAPHIC MULTISTATE MODELING OF ALZHEIMERS DISEASE

这项拟议的研究涉及阿尔茨海默病(AD)和缺血性心脏病(IHD)多状态模型的扩展。该模型旨在研究载脂蛋白-E基因(APOE)对这两种疾病风险的影响，但它可以适用于研究任何固定性状的影响。该模型对人口学和流行病学都具有重要的实践和理论意义。通过与已公布的数据进行拟合，证明了该模型的潜力。这项拟议的研究将把该模型应用于40项关于载脂蛋白E和AD关系的临床研究的原始数据。这些研究包括5939例AD患者和8746名对照。该提案包括该模型的六个应用和扩展：1)在欧洲起源的人群中研究载脂蛋白E在阿尔茨海默病中作用的性别差异。这将检验关于女性患AD风险较高的原因以及APOE基因在女性中降低AD风险差异的假设。2)利用该模型按病程和症状严重程度预测2030年的AD病例数。这将审查a)IHD死亡率预计下降的潜在影响，b)可能减缓AD进展的新疗法，以及c)可能推迟AD发病年龄的新方法。这方面的一个重要方面将是检查关于哪些APOE基因类型将从未来的发展中受益的不同假设的影响。3)编制一个更有效的计算机程序来估计模型的参数。该模型目前是在电子表格程序中编程的，该程序不能扩展以比较两个以上的人口。4)研究不同种族/民族的载脂蛋白E对AD影响的差异。之前的研究表明，APOE和AD白人、非裔美国人、西班牙裔美国人和日本人之间的关系存在很大差异。这项研究将测试关于AD病因的可能差异的假设，这些差异是风险模式的这些差异的基础。5)在接下来的几年里，AD的其他危险因素(特别是遗传危险因素)可能会有重大发现。这将使比较不同人群的研究和量化单个风险因素的重要性的过程复杂化。APOE和AD的模型将扩大，以包括额外的风险因素。

The proposed research involves extensions of a multi-state model of Alzheimer's disease (AD) and ischemic heart disease (IHD). The model is designed to study the effects of the Apolipoprotein-E gene (APOE) on the risks of both diseases, but it can be adapted to study the effects of any fixed traits. The model has important practical and theoretical implications for both demography and epidemiology. The potential of the model has been demonstrated by fitting it to published data. The proposed research will apply the model to raw data from 40 clinical studies of the relationship between APOE and AD. These studies include 5939 cases of AD and 8746 controls. The proposal includes six applications and extensions of the model: 1) A study of sex differentials in the role of APOE in AD in populations of European origin. This will test hypotheses about the causes of the higher risk of AD among women and the reduced differential in AD risk by APOE genotype among women. 2) Use the model to project the number of cases of AD to the year 2030 by duration of disease and severity of symptoms. This will examine the potential impact of a) projected declines in IHD mortality, b) likely new treatments to slow the progression of AD, and c) likely new approaches to delaying the age at onset of AD. An important aspect of this will be to examine the impact of different assumptions about which APOE genotypes will benefit from future developments. 3) Produce a more efficient computer program to estimate the parameters of the model. The model is currently programmed in a spreadsheet program which cannot be expanded to compare more than two populations. 4) Examine differences in the effects of APOE on AD by race/ethnicity. Previous research suggests there are large differences in the relationship between APOE and AD whites, African-Americans, Hispanics, and Japanese. This research will test hypotheses about the likely differences in the etiology of AD that underlie these differences in the patterns of risk. 5) It is likely that during the next few years there will be major findings of other risk factors (especially genetic risk factors) for AD. This will complicate the process of comparing studies across populations and quantifying the importance of individual risk factors. The model of APOE and AD will be expanded to include additional risk factors.