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相关痴呆(ADRD)会出现神经精神症状(NPS)。这些令人衰弱的症状 包括抑郁、焦虑、冷漠、妄想、幻觉、烦躁、睡眠障碍 疾病进展更快，功能障碍更大，照顾者负担更重，更早 制度化。目前治疗MCI/痴呆的NPS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NPS。 然而，我们对NPS在MCI/痴呆中的分子机制的提名有限。 治疗靶点。为了解决这个知识鸿沟，我们的目标是阐明基因和分子 用两种互补但独立的方法研究MCI/痴呆中NPS的潜在机制。 在第一种方法中，我们将利用NPS的坚实遗传基础(遗传率为~61%)来 识别与NPS相关的新基因。首先，我们将对核型多角体进行全基因组关联研究 来自全美的约32,000名MCI/AD/ADRD患者。我们将对每一种情况进行一次GWA NPS结构域以及所有NPS的多变量总和。每一次全球气候变化评估的结果都将被整合 参考人脑转录和蛋白质组学图谱以识别单个脑转录和 与NPS的因果关系一致的蛋白质。我们已将这些综合方法应用于AD 并确定了11个调节其大脑蛋白质丰度的基因，以易患AD(Wingo等人。2021年， NAT Genet)。与GWAS结果不同的是，这些发现指向特定的大脑蛋白质，这些蛋白质与 在AD中的因果作用。重要的是，这种方法并不完全依赖于全基因组的重要信号，而且 这一综合策略的因果推理已经经过实验测试，并被发现是稳健的。因此， 我们期望这一方法的发现将为NPS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、蛋白质和共表达网络 与NPS关联。我们将对死后的脑组织进行转录和蛋白质组测序 来自400名患有MCI/AD和纵向NPS评估的人，因为现有的脑组学数据没有 稳健的核动力源措施。然后，我们将在我们的差异中分别单独和整体检查NPS域 表达和网络分析。我们预计大脑转录本和蛋白质的分子变化 用这种方法确定的水平将为NPS的发病机制和进展提供洞察力。两者都研究 转录本和蛋白质将提供补充信息和更完整的分子图像。我们 认为了解蛋白质特别重要，因为它们是绝大多数药物靶标。 拟议的项目可能会导致对分子机制的新见解和新的治疗方法 为核动力源设定目标，从而对公共卫生产生重要和持久的影响。

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.