Understanding Alzheimer's Disease in the Context of the Aging

该项目的目标是显著提高我们对异类和共享机制的理解 正常衰老和阿尔茨海默病(AD)；识别可能防止与年龄相关的 大脑对AD的韧性和抵抗力下降，并验证AD的新候选基因靶点 使用AD病理学的临床前生物标记物进行预防/治疗。这一目标将使用数据来实现 收集了12项大型纵向和横断面人类研究的遗传和表型信息 总共有50多万个人。具体目标：1.确定新的多效性变异， 衰老和AD特征，并评估它们对AD风险和生存的联合影响。我们的假设是 与多种衰老和AD表型相关的多效性SNPs可能具有广泛的全身性 并共同影响阿尔茨海默病的风险和寿命。我们将选择这样的多效性SNP，使用 PheWas方法；评估它们对AD和生存特征的联合影响(相加和上位性)；选择最佳结果 并指定了富含各自基因的途径；并提出了连接这些基因的潜在机制 阿尔茨海默病的通路。结果的临床前验证将在目标3中完成。目标2.探索共享的生物学 衰老与阿尔茨海默病之间的机制及其遗传异质性，并确定新的候选基因 预防阿尔茨海默病的目标。我们的假设是，连接在同一途径上的基因与衰老和 相比来自不同途径的基因，AD更有可能共同影响相关的表型。我们将首先选择 代表与生理衰老有关的主要途径和过程的候选基因集 对损伤的恢复能力和对AD的抵抗力，基于目前来自人类和实验研究的证据。 然后我们将评估这些途径的基因对衰老和上位性的集体效应(相加和上位性)。 广告特点。TOP结果将在AIM 3中进一步验证。AIM 3.候选基因的临床前验证 在AIMS 1、2中选择的靶点，使用AD病理的生物标记物，并进一步探讨机制 基因关联的结果。进一步验证共同影响AD风险和/或的遗传变异集 在目标1和目标2中，我们将评估它们对AD病理的临床前生物标记物的联合影响，例如 海马体体积、脑脊液和代谢(FDG)生物标志物以及代谢组学特征，考虑其他 协变量。我们还将探讨目标1和目标2中发现的遗传因素之间的因果关系，以及 衰老和阿尔茨海默病的表型，使用孟德尔随机化和相关方法。本项目的成果 将显著提高我们对衰老和阿尔茨海默病的共同和不同机制的理解，以及 将有助于确定针对年龄的保护性遗传因素-大脑韧性和对AD的抵抗力下降，以及 为AD个体化预防和治疗提供新的基因靶点。

The project objective is to significantly improve our understanding of heterogeneous and shared mechanisms in normal aging and Alzheimer’s disease (AD); identify genetic factors that may protect against the age-associated declines in brain resilience and resistance to AD, and validate new candidate genetic targets for AD prevention/treatment using preclinical biomarkers of AD pathology. This objective will be addressed using data collected in twelve large longitudinal and cross-sectional human studies with genetic and phenotypic information on more than half a million individuals in total. Specific Aims: 1. Identify new pleiotropic variants that influence both aging and AD traits, and evaluate their joint impacts on AD risk and survival. Our hypothesis is that pleiotropic SNPs that are associated with multiple phenotypes of aging and AD may have a broad systemic influence on these traits and jointly affect AD risk and longevity. We will select such pleiotropic SNPs, using PheWas approach; evaluate their joint impacts (additive and epistatic) on AD and survival traits; select top results and specify pathways enriched in respective genes; and suggest potential mechanisms connecting these pathways with AD. Pre-clinical validation of the results will be done in Aim 3. Aim 2. Explore shared biological mechanisms between aging and AD, and their genetic heterogeneity, and identify new candidate genetic targets for AD prevention. Our hypothesis is that genes connected in the same pathway relevant to aging and AD will more likely jointly influence relevant phenotypes than genes from different pathways. We will first select sets of candidate genes representing major pathways and processes involved in physiological aging, brain resilience to damage and resistance to AD, based on current evidence from human and experimental studies. Then we will evaluate the collective effects (additive and epistatic) of genes from these pathways on aging and AD traits. Top results will be further validated in Aim 3. Aim 3. Preclinical validation of candidate genetic targets selected in Aims 1, 2, using biomarkers of AD pathology, and further exploration of mechanisms of genetic associations. To further validate sets of genetic variants that together influenced AD risk and/or survival in Aims 1 and 2, we will estimate their joint effects on preclinical biomarkers of AD pathology, such as hippocampal volume, CSF and metabolic (FDG) biomarkers, and metabolomics profiles, considering other covariates. We will also explore causal relationships between the genetic factors found in Aims 1 and 2, and phenotypes of aging and AD, using Mendelian Randomization and related approaches. Results of this project will significantly improve our understanding of the shared and heterogeneous mechanisms of aging and AD, and will help identify protective genetic factors against the age-declines in brain resilience and resistance to AD, and suggest new genetic targets for AD personalized prevention and treatment.