A brain multi-omic approach to identify key molecular drivers of neuropsychiatric symptoms in Alzheimer's dementia

大约65%的轻度认知障碍（MCI）、阿尔茨海默病（AD）或 AD相关性痴呆（ADRD）经历神经精神症状（CNS）。这些使人衰弱的症状 包括抑郁、焦虑、冷漠、妄想、幻觉、激动、睡眠障碍，并与 疾病进展更快，功能障碍更严重，护理人员负担更重， 制度化。目前治疗MCI/痴呆的药物疗效有限，但不良反应发生率高。 副作用，包括更高的死亡率。因此，迫切需要安全有效的治疗方法。 然而，我们对MCI/痴呆患者中BMPs的分子机制的了解有限， 治疗目标为了解决这一知识缺口，我们的目标是阐明遗传和分子 使用两种互补但独立的方法研究MCI/痴呆的潜在机制。 在第一种方法中，我们将充分利用遗传基础（遗传率约为61%）， 鉴定与大肠杆菌相关的新基因。首先，我们将进行全基因组关联研究（GWAS）， 在来自美国各地的约32，000名MCI/AD/ADRD患者中。我们将执行每个GWAS GWAS是一个多变量的GWAS。每个GWAS的结果将被整合 与参考人脑转录组学和蛋白质组学谱一起鉴定单个脑转录物， 这些蛋白质与致病性大肠杆菌是一致的。我们已经将这些综合方法应用于AD 并确定了11个调节大脑蛋白丰度从而使其易患AD的基因（Wingo等人，2021， Nat Genet）。与GWAS的结果不同，这些发现指向特定的大脑蛋白质，这些蛋白质与一个特定的基因一致。 在AD中的作用重要的是，这种方法不仅仅依赖于全基因组的显著信号， 这种综合策略的因果推理已经过实验测试，并被发现是稳健的。因此，在本发明中， 我们期望从这一方法中得到的发现将为研究乳腺癌的发病机制提供新的见解。 我们的第二种方法旨在识别大脑转录本、蛋白质和共表达网络 与相关。我们将对死后脑组织进行转录组和蛋白质组测序 从400名MCI/AD患者和纵向脑功能评估，因为现有的脑组学数据没有 强有力的预防措施。然后，我们将在我们的微分方程中单独和集体地研究非线性域。 表达和网络分析。我们预计，大脑转录物和蛋白质的分子改变 用这种方法确定的水平将提供对子宫内膜异位症发病机制和进展的了解。研究两者 转录物和蛋白质将提供互补信息和更完整的分子图像。我们 认为理解蛋白质是特别重要的，因为它们是绝大多数药物靶点。 拟议的项目可能会导致对分子机制和新的治疗方法的新见解 因此，对公共卫生产生重要和持续的影响。

Approximately 65% of individuals with mild cognitive impairment (MCI), Alzheimer's disease (AD), or AD related dementias (ADRD) experience neuropsychiatric symptoms (NPS). These debilitating symptoms include depression, anxiety, apathy, delusions, hallucinations, agitation, sleep disturbances and are associated with faster disease progression, greater functional impairment, higher caregiver burden, and earlier institutionalization. Current treatments for NPS in MCI/dementia have limited efficacy but high rates of adverse side effects, including higher mortality. Therefore, safe and effective treatments for NPS are urgently needed. However, we have limited insights into molecular mechanisms of NPS in MCI/dementia to nominate therapeutic targets. To address this knowledge gap, we aim to elucidate the genetic and molecular mechanisms underlying NPS in MCI/dementia using two complementary but independent approaches. In the first approach, we will leverage the substantial genetic basis of NPS (heritability of ~61%) to identify novel genes involved in NPS. First, we will perform genome-wide association studies (GWAS) of NPS in ~32,000 individuals with MCI/AD/ADRD from across the United States. We will perform a GWAS of each NPS domain as well as a multivariate GWAS of all NPS collectively. Results of each GWAS will be integrated with reference human brain transcriptomic and proteomic profiles to identify individual brain transcripts and proteins that are consistent with being causal in NPS. We have applied these integrative approaches to AD and identified 11 genes that regulate their brain protein abundances to predispose to AD (Wingo et al. 2021, Nat Genet). Unlike GWAS results, these findings point to specific brain proteins that are consistent with a causal role in AD. Importantly, this approach does not solely depend on genome-wide significant signals, and the causal inference of this integrative strategy has been experimentally tested and found to be robust. Thus, we expect that findings from this approach will provide novel insights into the pathogenesis of NPS. Our second approach aims to identify brain transcripts, proteins, and co-expression networks associated with NPS. We will perform transcriptomic and proteomic sequencing of post-mortem brain tissues from 400 individuals with MCI/AD and longitudinal NPS assessment, as existing brain omics data do not have robust NPS measures. Then we will examine NPS domains individually as well as collectively in our differential expression and network analyses. We anticipate that molecular alterations at the brain transcript and protein levels identified with this approach will provide insights into NPS pathogenesis and progression. Studying both transcripts and proteins would provide complementary information and a more complete molecular picture. We view understanding proteins as particularly important since they are the vast majority of drug targets. The proposed project will likely lead to new insights into molecular mechanisms and novel therapeutic targets for NPS and thereby have an important and sustained impact on public health.