Brain Vulnerability in Delirium and Alzheimer’s Disease and Related Dementias: Intersection of Polygenic Risk and Inflammation

项目摘要/摘要 这项提议的目标是检验阿尔茨海默氏症和阿尔茨海默氏症的遗传风险这一假设 疾病相关痴呆症(AD/ADRD)指的是患有“脆弱大脑”的人，他们可能是 易导致不良后果，包括精神错乱、认知功能减退和AD/ADRD 炎症性侮辱(如手术或感染)。精神错乱和AD/ADRD具有很强的流行病学 联系：AD/ADRD长期以来一直被认为是精神错乱的危险因素，最近精神错乱 被牵连为AD/ADRD事件的风险因素。尽管这表明精神错乱和 AD/ADRD，这些关系背后的共同病理生理学在很大程度上仍不清楚。生长 有证据表明，炎症是精神错乱和AD/ADRD的常见生物学机制，但不是全部 高度炎症的人会出现神志不清和/或AD/ADRD。因此，其他易感因素 (可能是遗传的)可能会影响炎症对大脑的影响。在拟议的R01具体目标中， 我们将解决这一知识差距，并通过以下方式大幅扩展我们之前的研究：1)超越单一 检验多个遗传座位协同效应(例如，多基因风险)的候选基因方法 分数，被显示为增强AD/ADRD的临床预测)，以及2)考虑AD/ADRD的多基因风险 炎症相互作用，增加了精神错乱、认知能力下降和AD/ADRD的风险。这些研究将 利用六个数据集的大量资源：(1和2)NIA资助的计划项目，成功的 择期手术后衰老研究(SAGES；P01AG031720)I及其更新SAGS II，(3)Intuit [调查术后脑连接性变化背后的神经炎症，术后 认知功能障碍，老年人的妄想症；K76-AG057022和UH2/3 AG056925]，(4)MADCO-PC [阿尔茨海默病的标志物与围手术期护理后的认知结果]，(5)大理石[调节 APOE信号可减少脑部炎症、精神错乱和术后认知功能障碍； R03AG050918]；以及6)以人口为基础的英国生物库，这是一大群已经 已经进行了基因分型。这一建议在检查多基因风险分数及其与 多个数据集中的炎症反应，包含有关妄想症和AD/ADRD的信息(在大多数研究中不可用)。 重要的是，研究结果将指导有针对性的、基于病理生理学的治疗，以提供神经保护。 对于脆弱的老年人，从而有可能防止精神错乱和减少AD/ADRD，对 所有老年人的独立性和生活质量。

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to test the hypothesis that genetic risk for Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD) identifies individuals with a “vulnerable brain,” who may be predisposed to bad outcomes, including delirium, cognitive decline, and AD/ADRD, in the presence of an inflammatory insult (e.g., surgery or infection). Delirium and AD/ADRD have strong epidemiological associations: AD/ADRD has long-been recognized as a risk factor for delirium, and recently delirium has been implicated as a risk factor for incident AD/ADRD. Although this points to a clear link between delirium and AD/ADRD, the shared pathophysiology underlying these relationships remains largely unknown. Growing evidence highlights inflammation as a common biological mechanism of delirium and AD/ADRD, but not all individuals with high inflammation develop delirium and/or AD/ADRD. Therefore other predisposing factors (possibly genetic) likely influence the effect of inflammation on the brain. In the proposed R01 Specific Aims, we will address this gap in knowledge and substantially extend our prior studies by: 1) moving beyond single candidate gene approaches to examine the synergistic effects of multiple genetic loci (e.g., polygenic risk scores, shown to enhance clinical prediction of AD/ADRD), and 2) consider how polygenic risk of AD/ADRD and inflammation interact to increase risk of delirium, cognitive decline, and AD/ADRD. These studies will leverage the considerable resources of six datasets: (1 & 2) the NIA-funded program project, the Successful Aging after Elective Surgery Study (SAGES; P01AG031720) I and its renewal SAGES II, (3) INTUIT [Investigating NeuroinflammaTion UnderlyIng Postoperative Brain Connectivity Changes, Postoperative CogniTive Dysfunction, Delirium in Older Adults; K76-AG057022 and UH2/3 AG056925], (4) MADCO-PC [Markers of Alzheimer’s Disease and Cognitive Outcomes after Perioperative Care], (5) MARBLE [Modulating ApoE signaling to Reduce Brain inflammation, deLirium, and postopErative cognitive dysfunction; R03AG050918]; and 6) the population-based UK Biobank, a large cohort of older adults who have already been genotyped. This proposal is highly novel in examining polygenic risk scores and their relationship with inflammation in multiple datasets with information on delirium and AD/ADRD (unavailable in most studies). Importantly, the results will inform targeted, pathophysiologically-based treatments to provide neuroprotection for vulnerable older adults, thereby potentially preventing delirium and reducing AD/ADRD, two major threats to the independence and quality of life of all older adults.