ApoE2 and protective molecular signatures in Alzheimer's disease and aging

ApoE2 和阿尔茨海默病和衰老中的保护性分子特征

• 批准号: 10425329
• 负责人: ALEXANDER M KULMINSKI
• 金额: $ 76.72万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425329
• 关键词: 19q13; Address; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease risk; Autopsy; Bioinformatics; Biological; Biology; Birth; Body mass index; Characteristics; Cholesterol; Complex; Data; Education; Environmental Exposure; Genes; Genetic; Genetic Transcription; Genotype; Haplotypes; Heterogeneity; High Density Lipoproteins; Human; Hypertension; Individual; Life; Linkage Disequilibrium; Lipids; Longevity; Low-Density Lipoproteins; Mediation; Molecular Analysis; Molecular Profiling; Non-Insulin-Dependent Diabetes Mellitus; Onset of illness; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Pilot Projects; Predisposition; Proxy; Quantitative Trait Loci; Research; Risk Factors; Role; Sampling; Statistical Methods; Structure; Tissues; Triglycerides; Variant; Work; apolipoprotein E-4; cardiovascular disorder risk; cognitive performance; cohort; density; exome; genetic epidemiology; genetic linkage analysis; improved; indexing; innovation; insight; lipoprotein cholesterol; novel strategies; personalized therapeutic; pleiotropism; protective allele; protective effect; reproductive; sex; statistics; trait; whole genome

Previous research emphasizes pleiotropic effects of the APOE 19q13.3 region variants supporting protective (notably, the APOE e2 allele) and detrimental (the APOE e4 allele) roles in Alzheimer’s disease (AD) and aging. Despite nearly two-decade progress in the APOE research, however, even pathogenic role of the strongest risk factor for AD, the APOE e4 allele, remains poorly understood. Understanding protective role of the e2 allele is lagged behind the APOE e4 research due to, in part, seemingly smaller effects of this allele on AD. This paradoxical situation of a potentially strong role of the APOE locus in AD and aging, and a hampered progress in the ApoE2-Aging-AD research requires new approaches. Our approach is built on core principles of evolutionary biology in genetics of aging- related traits characteristic for post-reproductive life, insights from genetic epidemiology of such traits, and the results of our large-scale pilot study of five human cohorts proving its significance and feasibility. The core of our approach is the association of AD with complex molecular signatures in the APOE region, rather than with a single allele, which include the e2 allele. These signatures are defined by significant differences in linkage disequilibrium (LD) patterns between affected and unaffected subjects. The principal difference between our approach and previous studies of LD structures in the APOE region, making it highly innovative, is that following the core biological principles in genetics of aging- related traits, the effects in the ApoE2-Aging-AD framework are considered to be associated with AD- specific molecular signatures, rather than with those driven by common evolutionarily forces. This difference justifies the focus on extended signatures comprised of the APOE e2 allele and SNPs spread through the entire genome and interacting with this allele. Analysis of molecular signatures provides invaluable opportunity to dissect heterogeneity in action of the APOE e2 allele by identifying personalized (i.e., more homogeneous, group specific) polygenic profiles with stronger protective effect of this allele. The objective of this proposal is to identify personalized polygenic profiles, comprised of the e2 allele, other SNPs in the APOE region, and SNPs spread through the entire genome, with stronger protection in the ApoE2-Aging-AD framework, and identify the role of AD risk factors in these profiles. Specific aims: Aim 1. Identify molecular signatures of AD and life span as a proxy for aging. Aim 2. Dissect heterogeneity and identify commonalities in the molecular signatures. Aim 3. Identify personalized polygenic profiles of AD and aging traits. Aim 4. Use bioinformatics analysis to characterize functional consequences of SNPs and genes.

先前的研究强调 APOE 19q13.3 区域变异的多效性支持 阿尔茨海默病中的保护作用（尤其是 APOE e2 等位基因）和应激作用（APOE e4 等位基因） 然而，尽管 APOE 研究取得了近二十年的进展，但 AD 最强危险因素 APOE e4 等位基因的致病作用仍知之甚少。 对 e2 等位基因的保护作用的了解落后于 APOE e4 研究，部分原因是： 该等位基因对 AD 的潜在作用似乎较小，但这种矛盾的情况却具有潜在的强大作用。 AD 和衰老中的 APOE 位点，以及 ApoE2-Aging-AD 研究进展受阻，需要 我们的方法建立在衰老遗传学进化生物学的核心原理之上。 生殖后生命特征的相关特征，这些特征的遗传流行病学的见解， 我们对五个人类队列进行的大规模试点研究的结果证明了其重要性和可行性。 我们方法的核心是将 AD 与 APOE 中复杂的分子特征联系起来 区域，而不是单个等位基因，其中包括 e2 等位基因。 受影响和未受影响受试者之间的连锁不平衡（LD）模式存在显着差异。 我们的方法与之前的 APOE LD 结构研究之间的主要区别 使其具有高度创新性的地区，是遵循衰老遗传学的核心生物学原理- 相关特征，ApoE2-Aging-AD 框架中的影响被认为与 AD- 特定的分子特征，而不是由共同的进化力量驱动的分子特征。 差异证明了对由 APOE e2 等位基因和 SNP 传播组成的扩展特征的关注是合理的 通过整个基因组并与该等位基因相互作用的分子特征分析提供了。 通过识别 APOE e2 等位基因的作用来剖析异质性的宝贵机会 具有更强保护作用的个性化（即更同质、群体特异性）多基因图谱 该提案的目的是确定个性化的多基因谱，包括： e2 等位基因、APOE 区域中的其他 SNP 以及遍布整个基因组的 SNP， ApoE2-Aging-AD 框架中更强的保护，并确定 AD 风险因素在这些中的作用 具体目标： 目标 1. 确定 AD 的分子特征和寿命作为衰老的指标。 目标 2. 剖析异质性并识别分子特征中的共性。 目标 3. 识别。 AD 和衰老特征的个性化多基因图谱 目标 4. 使用生物信息学分析 表征 SNP 和基因的功能后果。