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构和共享机制的理解， 正常衰老和阿尔茨海默病（AD）;确定可能保护免受年龄相关疾病的遗传因素 大脑弹性和对AD的抵抗力下降，并验证AD的新候选遗传靶点 使用AD病理学的临床前生物标志物预防/治疗。这一目标将通过数据来实现。 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， 总共超过50万人。具体目标：1。识别影响的新的多效性变体 老化和AD性状，并评估其对AD风险和生存的联合影响。我们的假设是 与衰老和AD的多种表型相关的多效性SNP可能具有广泛的系统性 影响这些特征，并共同影响AD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和存活性状的联合影响（加性和上位性）;选择最佳结果 并指定在各自基因中富集的途径;并提出连接这些途径的潜在机制 AD的路径。将在目标3中对结果进行临床前确认。目标二。探索共享的生物 衰老和AD之间的机制，以及它们的遗传异质性，并确定新的候选基因 预防AD的目标。我们的假设是，与衰老相关的同一途径中的基因， AD将更有可能共同影响相关的表型比基因从不同的途径。我们将首先选择 代表生理老化、脑老化、脑老化和脑老化的主要途径和过程的候选基因组。 根据目前人类和实验研究的证据，对损害的恢复力和对AD的抵抗力。 然后，我们将评估来自这些途径的基因对衰老的集体效应（加性和上位性）， AD特征。最佳结果将在目标3中进一步验证。目标3.候选基因的临床前验证 目的1、2中选择的靶点，使用AD病理学的生物标志物，并进一步探索机制 基因关联。为了进一步验证共同影响AD风险的遗传变异集和/或 在目标1和2中，我们将评估它们对AD病理学的临床前生物标志物的联合作用，例如 海马体积、CSF和代谢（FDG）生物标志物以及代谢组学特征，同时考虑其他 协变量我们还将探讨目标1和2中发现的遗传因素之间的因果关系， 表型的老化和AD，使用孟德尔随机化和相关的方法。本项目的成果 将显著提高我们对衰老和AD的共享和异质机制的理解， 将有助于确定保护性遗传因素，防止大脑弹性和抗AD能力的年龄下降， 为AD个性化预防和治疗提供了新的遗传靶点。

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.