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

项目总结/摘要 这项提案的目的是检验阿尔茨海默病和阿尔茨海默病的遗传风险 疾病相关性痴呆（AD/ADRD）识别出具有“脆弱大脑”的个体， 易发生不良结局，包括谵妄、认知下降和AD/ADRD， 炎性损伤（例如，手术或感染）。谵妄和AD/ADRD具有很强的流行病学特征， 相关性：AD/ADRD长期以来被认为是谵妄的危险因素，最近谵妄已被 可能是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仍然在很大程度上未知。增长 证据强调炎症是谵妄和AD/ADRD的常见生物学机制，但不是所有 具有高度炎症的个体发展为谵妄和/或AD/ADRD。因此，其他诱发因素 （可能是遗传的）可能会影响炎症对大脑的影响。在拟议的R 01具体目标中， 我们将解决这一知识差距，并通过以下方式大大扩展我们先前的研究：1）超越单一的 检测多个遗传基因座的协同效应的候选基因方法（例如，多基因风险 评分，显示可增强AD/ADRD的临床预测），以及2）考虑AD/ADRD的多基因风险 和炎症相互作用，增加谵妄、认知能力下降和AD/ADRD的风险。这些研究将 利用六个数据集的可观资源：（1和2）NIA资助的计划项目，成功的 择期手术后老化研究（SAGES; P01 AG 031720）I及其更新SAGES II，（3）INTUIT [研究术后脑连通性变化背后的神经炎症，术后 认知功能障碍，老年人谵妄; K76-AG 057022和UH 2/3 AG 056925]，（4）MADCO-PC [阿尔茨海默病的标志物和围手术期护理后的认知结果]，（5）MARBLE [调节 ApoE信号转导减少脑炎症、谵妄和术后认知功能障碍; R 03 AG 050918];以及6）基于人群的英国生物库，一个大型的老年人队列，他们已经 被基因分型。这一建议在研究多基因风险评分及其与 炎症与谵妄和AD/ADRD的信息（在大多数研究中不可用）的多个数据集。 重要的是，这些结果将为靶向的、基于病理生理学的治疗提供信息，以提供神经保护 对于脆弱的老年人，从而有可能预防谵妄和减少AD/ADRD，这是两个主要的威胁， 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.