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

先前的研究强调APOE 19q13.3区域变异的多效性效应，支持 阿尔茨海默病的保护性(特别是载脂蛋白e2等位基因)和有害(载脂蛋白e4等位基因)的作用 疾病(AD)和衰老。然而，尽管APOE研究取得了近20年的进展，但即使 阿尔茨海默病的最强危险因素--APOE e4等位基因的致病作用尚不清楚。 对e2等位基因的保护作用的了解落后于apoE e4的研究，部分原因是 该等位基因对阿尔茨海默病的影响似乎较小。这一矛盾的情况下，一个潜在的强大的作用 AD和衰老中的APOE基因座，以及APOE2-Aging-AD研究进展受阻需要 新方法。我们的方法建立在衰老遗传学中进化生物学的核心原则上-- 生殖后生活的相关特征，对这些特征的遗传流行病学的见解， 我们对五个人群进行的大规模先导性研究的结果证明了它的意义和可行性。 我们方法的核心是AD与APOE中复杂的分子签名的关联 区域，而不是只有一个等位基因，包括e2等位基因。这些签名由定义 连锁不平衡(LD)模式在受影响和未受影响的受试者之间存在显著差异。 我们的方法与以前对APOE中LD结构的研究的主要区别 区域，使其具有高度的创新性，是遵循衰老遗传学的核心生物学原理- 相关性状，APOE2-Aging-AD框架中的效应被认为与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。这 差异证明了关注由apoE e2等位基因和SNPs传播组成的扩展签名是合理的 通过整个基因组并与这个等位基因相互作用。分子签名的分析提供了 通过鉴定apoE e2等位基因的作用来剖析其异质性的宝贵机会 具有更强保护作用的个性化(即，更同质、特定于群体)多基因图谱 这个等位基因。这项建议的目标是确定个性化的多基因图谱，包括 E2等位基因、APOE区域的其他SNPs和SNPs遍布整个基因组， 在APOE2-Aging-AD框架中提供更强大的保护，并确定AD风险因素在这些方面的作用 配置文件。具体目的：目的1.确定AD的分子特征和寿命作为衰老的指标。 目的2.剖析分子特征中的异质性并确定其共性。目标3.确定 阿尔茨海默病与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 描述SNPs和基因的功能后果。

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.