APOE genotype and diet influences on Alzheimer's biomarkers

 描述(申请人提供)：以高饱和脂肪和高血糖指数食物为特征的“西方饮食”(高饮食)是阿尔茨海默病(AD)的危险因素。然而，我们发现矛盾的是，用西式高饮食进行实验性喂养可以显著改善APOE E4携带者的认知能力，他们患AD的风险更高。本项目的目的是审查这种反应的基础机制。根据已知的E4携带者脑化学成分的内在差异，我们假设在这一组中，高膳食将导致脑内脂质和胰岛素运输增加，ApoE脂化增加，脑淀粉样蛋白清除增加，最终改善认知。我们将通过在老年人中进行交叉设计的受控膳食挑战来检验这些假设，这些老年人既有高膳食，也有低饱和脂肪和血糖指数食物(低)。餐后，参与者将接受认知测试，并收集血液和脊髓液，以分析血脂、胰岛素和已知的AD生物标记物。这项工作将有助于我们更广泛地了解饮食和AD的风险，以及APOE基因如何缓解这种风险。除了增进我们对AD发病机制的理解外，这个职业发展奖将给我必要的工具，使我成为代谢和阿尔茨海默病领域的独立临床研究员。

 DESCRIPTION (provided by applicant): The 'Western diet' which is characterized by high saturated fat and high glycemic index foods (high diet) is a risk factor for Alzheimer's disease (AD). However, we have found paradoxically that experimental feeding with a Western style high diet acutely improves cognition in APOE E4 carriers, who are at increased risk for AD. The purpose of this project is to examine mechanisms that underlie this response. Based on known intrinsic differences in brain chemistry in E4 carriers, we hypothesize that in this group, a high meal will result in increased brain transport of lipids and insulin, increased ApoE lipidation, increased brain amyloid clearance, and ultimately improved cognition. We will test these hypotheses by conducting a controlled meal challenge in a crossover design in older adults with both a high meal, as well as a meal low in saturated fat and glycemic index foods (low). After the meal, participants will undergo cognitive testing and collection of blood and spinal fluid for analysis of lipids, insulin, and known AD biomarkers. This work will contribute to our broader understanding about the risks of diet and AD, and how APOE genotype moderates that risk. In addition to advancing our understanding about AD pathogenesis, this career development award will give me the necessary tools to become an independent clinical investigator in the field of metabolism and Alzheimer's disease.