Understanding the molecular mechanisms of Depression and Psychological Well-being in Alzheimer's disease

心理健康（PWB）和抑郁是改变阿尔茨海默氏症风险的重要因素 疾病（AD），一种记忆和认知的进行性侵蚀的病症。具体来说，抑郁症是 与AD痴呆的风险增加相关，而PWB在控制了以下因素后与AD风险降低相关： 萧条然而，这些重要关联的分子机制尚不清楚， 这一提案的重点。根据我们和其他人的研究中出现的证据，我们假设， 关键microRNAs（miRNAs）的表达改变有助于抑郁症和PWB对AD风险的影响。 为了验证这一假设，我们建议研究一个独特的数据集，该数据集包含850个人类死后大脑， 拉什记忆和老化项目（MAP）。这项前瞻性纵向研究每年收集以下数据： 抑郁症、PWB、认知、身体健康和痴呆，以及基因组、转录组和蛋白质组数据 背外侧前额叶皮层（dPFC）。我们提出了一个2阶段的遗传研究，以确定关键的miRNAs， 转录本，与抑郁症相关的蛋白质，并分别与PWB，并检查他们如何联系 认知改变、AD痴呆和痴呆相关病理。我们的发现数据集将是 将MAP样本和复制集的250份MAP样本，随后联合分析全部850份。 在目标1中，我们提出通过以下方法分别鉴定抑郁症和PWB特异性的miRNAs： 全基因组miRNA表达分析。然后我们将确定这些miRNAs如何与AD相关 表型（即认知能力下降率、痴呆临床诊断和痴呆相关病理）。 我们预期鉴定出与抑郁症和AD显著相关的miRNA（称为Dep-AD-miRNA）。 miRNA），以及PWB和AD两者（PWB-AD-miRNA）。在目标2中，我们检查了目标的转录水平， Dep-AD-miRNAs和PWB-AD-miRNAs在AD表型中的表达。我们假设这些基因的mRNA水平 靶点将与AD表型相关。此外，我们将对以下基因进行共表达网络分析： 现有的转录组来鉴定抑郁症和PWB的表达模块和关键表达驱动因子， 分开然后，我们将测试这些关键表达驱动因素是否与AD表型相关。在目标3中， 将检测AD中Dep-AD-miRNAs和PWB-AD-miRNAs下游靶标的蛋白水平 表型。我们还测试了来自Aim 2的重要转录本的蛋白水平是否与以下因素相关： AD表型。最后，我们将对现有的全球蛋白质组进行网络分析，以识别新的蛋白质组。 抑郁症和PWB的蛋白质组驱动程序，分别研究它们与AD表型的关联。 该项目可以潜在地识别AD痴呆症的重要分子贡献者，这些分子贡献者可能不是 通过其他方法显而易见，导致对AD机制和治疗靶点的新见解， 从而对公共卫生产生重要和持续的影响。

Psychological well-being (PWB) and depression are important factors that modify risk for Alzheimer's disease (AD), a disorder of progressive erosion of memory and cognition. Specifically, depression is associated with increased risk for AD dementia while PWB with decreased risk for AD after controlling for depression. Molecular mechanisms underlying these important associations, however, are not known and are the focus of this proposal. Based on emerging evidence from our studies and others', we hypothesize that altered expression of key microRNAs (miRNAs) contribute to the effects of depression and PWB on AD risk. To test this hypothesis we propose to study a unique dataset of 850 human postmortem brains from the Rush Memory and Aging Project (MAP). This prospective longitudinal study annually collects data on depression, PWB, cognition, physical health, and dementia, and genomic, transcriptomic, and proteomic data from the dorsolateral prefrontal cortex (dPFC). We propose a 2-stage genetic study to identify key miRNAs, transcripts, and proteins associated with depression, and separately with PWB, and examine how they relate to cognitive change, AD dementia, and dementia-related pathologies. Our discovery dataset will be the 600 MAP samples and replication set will be 250 MAP samples, followed by a joint analysis of all 850. In Aim 1 we propose to identify miRNAs specific to depression and PWB, respectively, through genome-wide miRNA expression analyses. We will then determine how these miRNAs are associated with AD phenotypes (i.e. rate of cognitive decline, clinical diagnosis of dementia, and dementia-related pathologies). We anticipate identifying miRNAs significantly associated with both depression and AD (referred to as Dep-AD- miRNAs), and to both PWB and AD (PWB-AD-miRNAs). In Aim 2, we examine transcript levels of the targets of the Dep-AD-miRNAs and PWB-AD-miRNAs in AD phenotypes. We hypothesize that mRNA levels of these targets will be associated with AD phenotypes. Additionally, we will perform co-expression network analysis on existing transcriptomes to identify expression modules and key expression drivers for depression and PWB, separately. We will then test if these key expression drivers are associated with AD phenotypes. In Aim 3, we will examine protein levels of the downstream targets of the Dep-AD-miRNAs and PWB-AD-miRNAs in AD phenotypes. We also test whether protein levels of the significant transcripts from Aim 2 are associated with AD phenotypes. Lastly, we will perform network analysis on existing global proteomes to identify novel proteomic drivers for depression and PWB, respectively, and examine their association with AD phenotypes. This project can potentially identify important molecular contributors of AD dementia that might not be apparent through other approaches, leading to new insights into mechanisms and treatment targets for AD and thereby have an important and sustained impact on public health.