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）：成年后期的规范性认知变化和阿尔茨海默病（AD）的病因尚未完全了解。在编码apoE的基因之外，一致的候选基因关联相对较少。APOE（大脑中主要的胆固醇转运蛋白）的遗传变异对血脂水平、认知变化和AD风险的既定影响表明，胆固醇途径可能具有重要的中枢作用。我们建议以胆固醇稳态不可或缺的基因为靶点，并进行多层关联研究，以调查功能基因组序列变异对血脂参数、CSF Abeta和tau、纵向认知能力指标和阿尔茨海默病（AD）的可能存在和影响。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所选的候选基因中，并将解释各种胆固醇相关表型的差异，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。几项相关的瑞典双胞胎纵向研究将结合起来，以测试与血清脂质生物标志物，认知能力下降，总痴呆和AD风险的相关性。此外，我们将使用大量成熟的瑞典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人（59%为女性）可用于DMA标记物分析，其中1，227人诊断为AD。在那些有DNA的双胞胎中，有676对双胞胎有可用的脂质生物标志物，729对双胞胎有可用的认知数据。我们的目标是逐步从匿名方差分量到胆固醇途径中的测量基因、中间生物标志物以及最终的行为和临床表型。主要利益是：（1）测试胆固醇基因标志物与血清脂质和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志物与跨越语言、空间、记忆和感知速度域的认知下降的关联;以及（3）测试胆固醇基因标志物、总痴呆和AD风险的关联。我们将应用单倍型和多位点回归方法来确定关联。该研究的优势包括多层次的重复和丰富的纵向数据，无论是血脂还是认知特征。使用基于双胞胎和病例对照的方法对胆固醇途径中的多个候选基因进行检查，将导致对导致认知变化，总痴呆和老年AD风险的因素的更多了解。