Cholesterol metabolism pathway: Cognitive change and Alzheimer's disease risk

胆固醇代谢途径：认知变化和阿尔茨海默病风险

• 批准号: 7265691
• 负责人: CHANDRA A REYNOLDS
• 金额: $ 40.65万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7265691
• 关键词: Adoption; Affect; Age; Age of Onset; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amino Acids; Amyloid beta-Protein; Apolipoprotein E; Behavioral; Biochemistry; Biological Markers; Brain; California; Candidate Disease Gene; Case-Control Studies; Cerebrospinal Fluid; Cholesterol; Cholesterol Homeostasis; Cognitive; Collaborations; Complement; Computer Simulation; DNA; Data; Dementia; Diagnosis; Disease regression; Elderly; End Date; Ensure; Etiology; Female; Funding; Gender; Gene Targeting; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Genotype; Goals; Grant; Growth; Haplotypes; Human; Impaired cognition; Individual; International; Lead; Linkage Disequilibrium; Lipids; Measures; Memory; Methods; Modeling; Molecular; Outcome; Pathway interactions; Performance; Phenotype; Plasma; Population; Psyche structure; Quantitative Genetics; RNA Splicing; Registries; Research Activity; Research Personnel; Sampling; Selection Criteria; Series; Serum; Sex Characteristics; Siblings; Site; Source; Speed; Testing; Time; Twin Multiple Birth; Twin Studies; Universities; Variant; Work; base; case control; cholesterol transporters; clinical phenotype; cognitive change; cost; functional genomics; gene interaction; genetic association; insertion/deletion mutation; interest; processing speed; programs; tau Proteins; tool; trait

DESCRIPTION (provided by applicant): The etiologies of normative cognitive change and Alzheimer's disease (AD) in late adulthood are not fully understood. Outside of the gene encoding apoE, consistent candidate gene associations are relatively scant. Established effects of genetic variation in APOE, the primary cholesterol transporter in the brain, upon lipid levels, cognitive change, and AD risk suggest the cholesterol pathway may be centrally important. We propose to target genes integral to cholesterol homeostasis and perform multi-tiered association studies to investigate the possible existence and impact of functional genomic sequence variation on plasma lipid parameters, CSF Abeta and tau, measures of longitudinal cognitive performance, and Alzheimer's disease (AD). We have prioritized 502 genetic markers, focusing on HapMap based markers as well as potential functional polymorphisms within 20 cholesterol genes. We hypothesize that functional genetic polymorphism occurs in the selected candidate genes and will explain variance in a variety of cholesterol related phenotypes, with stronger effects upon proximal phenotypes (e.g. cholesterol and Abeta levels) than for cognitive phenotypes and AD risk. Several related longitudinal Swedish twin studies will be combined to test association with serum lipid biomarkers, cognitive decline, total dementia and AD risk. Additionally, we will use a large established Swedish AD case-control sample for testing additional biomarkers (CSF Abeta, tau) and AD risk. Across twin and case-control studies there are 3,858 of individuals (59 percent female) available for analysis of DMA markers, 1,227 with AD diagnoses. Of those with DNA, there are 676 twin pairs with available lipid biomarkers and 729 twin pairs with available cognitive data. Our goals are to move stepwise from anonymous variance components to measured genes in the cholesterol pathway, intermediate biomarkers, and ultimate behavioral and clinical phenotypes. Of principal interest is to: (1) test the association of cholesterol gene markers with serum lipid and CSF biomarkers; (2) test the association of lipid biomarkers and cholesterol gene markers with cognitive decline across verbal, spatial, memory and perceptual speed domains, using longitudinal growth models to quantify change; and (3) test Jhe association of cholesterol gene markers, total dementia and AD risk. We will apply haplotype and multi-locus regression approaches to determine association. Strengths of the study include multiple levels of replication and rich longitudinal data, both for lipid and cognitive traits. The examination of multiple candidate genes in the cholesterol pathway, using both twin-based and case-control methods, will lead to an increased understanding of factors that contribute to cognitive changes, total dementia and AD risk in late-life.

描述（由申请人提供）：成年后期规范认知变化和阿尔茨海默氏病（AD）的病因尚不完全了解。在编码APOE的基因之外，一致的候选基因关联相对很少。 APOE的遗传变异的确定作用，大脑中的主要胆固醇转运蛋白对脂质水平，认知变化和AD风险的影响表明胆固醇途径可能非常重要。我们建议靶向胆固醇稳态不可或缺的基因，并进行多层关联研究，以研究功能基因组序列变化对血浆脂质参数，CSF Abeta和Tau的可能存在和影响，纵向认知性能的测量以及阿尔茨海默氏病（AD）。我们优先考虑了502个遗传标记，重点是基于HAPMAP的标记以及20个胆固醇基因内的潜在功能多态性。我们假设功能性遗传多态性发生在选定的候选基因中，并将解释各种胆固醇相关的表型的方差，对近端表型（例如胆固醇和ABETA水平）的影响比认知表型和AD风险更强。几项相关的纵向瑞典双胞胎研究将结合到与血清脂质生物标志物，认知能力下降，总痴呆症和AD风险的结合。此外，我们将使用大型瑞典AD病例对照样本来测试其他生物标志物（CSF Abeta，Tau）和AD风险。在双胞胎和病例对照研究中，有3,858个个体（59％的女性）可用于分析DMA标记，1,227个具有AD诊断的人。在具有DNA的人中，有676对具有可用脂质生物标志物的双胞胎和729对具有可用认知数据的双胞胎。我们的目标是逐步从匿名方差成分逐步转移到胆固醇途径，中间生物标志物以及最终行为和临床表型中测得的基因。主要兴趣是：（1）测试胆固醇基因标记与血清脂质和CSF生物标志物的关联； （2）使用纵向生长模型来量化变化，测试脂质生物标志物和胆固醇基因标记物与言语，空间，记忆和感知速度域之间认知能力下降的关联； （3）测试JHE胆固醇基因标记，痴呆症和AD风险的协会。我们将采用单倍型和多层次回归方法来确定关联。该研究的优势包括用于脂质和认知性状的多个级别的复制和丰富的纵向数据。使用基于双基因和病例对照方法对胆固醇途径中多个候选基因的检查将提高人们对有助于认知变化，痴呆症总和AD风险的因素的更多了解。