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

描述(由申请人提供)：成人后期的标准化认知改变和阿尔茨海默病(AD)的病因尚未完全了解。在编码载脂蛋白E的基因之外，一致的候选基因关联相对较少。脑中主要的胆固醇转运体载脂蛋白E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，胆固醇途径可能是中心重要的。我们建议以胆固醇稳态所必需的基因为靶点，并进行多层次关联研究，以调查功能基因组序列变异对血浆脂质参数、脑脊液Abeta和tau、纵向认知能力的测量以及阿尔茨海默病(AD)的可能存在和影响。我们已经优先考虑了502个遗传标记，重点是基于HapMap的标记以及20个胆固醇基因中潜在的功能多态。我们假设功能性遗传多态性发生在选定的候选基因中，并将解释各种与胆固醇相关的表型的差异，与认知表型和AD风险相比，对近端表型(如胆固醇和Abeta水平)的影响更大。几项相关的瑞典双胞胎纵向研究将被结合起来，以测试与血脂生物标记物、认知能力下降、总痴呆症和AD风险的相关性。此外，我们将使用一个大型的瑞典AD病例对照样本来测试额外的生物标记物(脑脊液Abeta、tau)和AD风险。在双胞胎和病例对照研究中，有3858名个体(59%女性)可用于DMA标记分析，1227名患有AD诊断。在那些携带DNA的人中，有676对双胞胎拥有可用的脂质生物标记物，729对双胞胎拥有可用的认知数据。我们的目标是逐步从匿名的变异成分转移到胆固醇途径中的可测量基因、中间生物标记物以及最终的行为和临床表型。主要的兴趣是：(1)测试胆固醇基因标记物与血清脂质和脑脊液生物标记物的关联；(2)测试脂类生物标记物和胆固醇基因标记物与言语、空间、记忆和知觉速度域认知能力下降的关联，使用纵向增长模型量化变化；以及(3)测试胆固醇基因标记物、总痴呆症和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。这项研究的优势包括多水平的复制和丰富的纵向数据，包括血脂和认知特征。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，将有助于加深对导致认知变化、老年痴呆和AD风险的因素的理解。

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.