本课题旨在探索脂代谢基因（APOC1,CLU,SORL1和APOE）变异通过调控脂代谢和Aβ水平, 影响晚发型Alzheimer病（LOAD）的发病机理。拟在前期人群研究基础上，检测和比较LOAD及与其匹配的认知功能正常老年人脂代谢基因变异，Aβ40-42水平,疾病表型（LOAD分级，神经认知功能，脑影像）及临床和血液代谢指标，识别广西LOAD人群脂代谢风险基因变异和基因交互作用，及其对Aβ40-42水平,LOAD疾病/代谢表型的影响。然后，着重研究人群中的每一受试个体，经纵向队列随访比较有/无风险基因型携带对LOAD疾病/代谢表型变化的影响，并利用体外细胞模型探索LOAD发病过程识别的基因突变对Aβ生成和脂代谢影响的功能机制。最后，经人群,个体,细胞和分子研究的综合分析，获得脂代谢基因变异与LOAD疾病/代谢表型关联和影响LOAD发病机理的证据，该结果在诊治和预防方面具有潜在价值。

The objective of this application is to explore the effect of lipid metabolism and A beta (Aβ) level regulated by APOC1, CLU, SORL1 and APOE variances on late-onset alzheimer disease (LOAD) pathogenesis. Based on previous cross-sectional study in Guangxi, we intend to test and compare the variations of lipid metabolism related genes (APOC1,CLU,SORL1and APOE), levels of Aβ40-42, disease phenotype, such as LOAD degree, neurocognitive function, brain imaging and biological markers，as well as clinical and blood metabolic indicators between LOAD and cognitively normal elderly matched with LOAD, to access the impact of lipid metabolism related genes variations and their gene-gene interactions on the levels of Aβ40-42, as well as LOAD disease/metabolic phenotype in Guangxi. And then, we are going to focus on each subject to determine the relationship among risk genotypes, disease and metabolic phenotype though following up a Guangxi longitudinal LOAD cohort. We are also plan to establish an in vitro cell model to explore the functional mechanism of LOAD assciated gene variances on Aβ generation and lipid metabolism. Finally, we plan to find out the impact of lipid metabolism related genes variations on LOAD disease/metabolic phenotype, as well as LOAD pathogenesis through the research based on population, individual, cell and molecule.The research is expected to have potential application value in clinical diagnosis, intervention and prevention of LOAD.