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

谵妄、阿尔茨海默病和相关痴呆症中的大脑脆弱性：多基因风险与炎症的交叉点

• 批准号: 10559987
• 负责人: SARINNAPHA VASUNILASHORN
• 金额: $ 88.67万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559987
• 关键词: Acceleration; Acute; Adult; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Apolipoprotein E; Biological; Blood; Brain; C-reactive protein; Candidate Disease Gene; Catechol O-Methyltransferase; Clinical; Code; Cognition; Cognitive; Communities; Confusion; Creativeness; DNA Library; Data; Data Set; Delirium; Dementia; Development; Elderly; Encephalitis; Enrollment; Epidemiology; Functional disorder; Funding; Gene Proteins; Genetic; Genetic Materials; Genetic Risk; Genotype; Goals; Health; Hospitals; Impaired cognition; Individual; Infection; Inflammation; Inflammatory; Interleukin-6; International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10); Intervention; Knowledge; Link; Measures; Medical Records; Microglia; Modeling; Neurocognitive; Neurologic Dysfunctions; Operative Surgical Procedures; Outcome; Participant; Patients; Perioperative Care; Plasma; Postoperative Period; Predisposing Factor; Prevention; Quality of life; Research; Resources; Risk; Risk Factors; Sampling; Signal Transduction; Stress; Syndrome; Testing; Time; United Kingdom; Work; acute stress; aged; big biomedical data; biobank; biological adaptation to stress; clinical predictors; cognitive function; cohort; cost; follow-up; genetic information; genetic risk factor; genome sequencing; genome-wide; genomic locus; human old age (65+); inflammatory marker; multiple datasets; neuroinflammation; neuroprotection; novel; polygenic risk score; population based; post-operative cognitive dysfunction; postoperative delirium; prevent; programs; systemic inflammatory response

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.

项目概要/摘要 该提案的目的是检验以下假设：阿尔茨海默病和阿尔茨海默病的遗传风险 疾病相关痴呆症 (AD/ADRD) 识别出具有“脆弱大脑”的个体，这些人可能 容易出现不良后果，包括谵妄、认知能力下降和 AD/ADRD 炎症损伤（例如手术或感染）和 AD/ADRD 具有很强的流行病学特征。 协会：AD/ADRD 长期以来一直被认为是谵妄的危险因素，最近谵妄已被 尽管这表明谵妄和 ADRD 之间存在明显的联系，但它是 AD/ADRD 事件的危险因素。 AD/ADRD，这些关系背后的共同病理生理学在很大程度上仍然未知。 有证据表明炎症是谵妄和 AD/ADRD 的常见生物学机制，但并非全部 患有高炎症的个体会出现谵妄和/或 AD/ADRD。 （可能是遗传）可能会影响炎症对大脑的影响。在拟议的 R01 具体目标中， 我们将通过以下方式解决这一知识差距并大幅扩展我们之前的研究：1）超越单一 候选基因方法来检查多个遗传位点的协同效应（例如，多基因风险 分数，显示可以增强 AD/ADRD 的临床预测），以及 2) 考虑 AD/ADRD 的多基因风险如何 这些研究将增加谵妄、认知能力下降和 AD/ADRD 的风险。 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 选择性手术后老化研究 (SAGES; P01AG031720) I 及其更新 SAGES II, (3) INTUIT [调查术后大脑连接变化背后的神经炎症，术后 老年人认知功能障碍、谵妄；K76-AG057022 和 UH2/3 AG056925]，(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 信号传导可减少大脑炎症、谵妄和术后认知功能障碍； R03AG050918]；和 6) 以人口为基础的英国生物银行，一大群已经 该提案在检查多基因风险评分及其与疾病的关系方面非常新颖。 多个数据集中的炎症，包含有关谵妄和 AD/ADRD 的信息（大多数研究中不可用）。 重要的是，结果将为有针对性的、基于病理生理学的治疗提供信息，以提供神经保护 对于年长易受伤害的成年人，从而有可能预防谵妄并减少 AD/ADRD，这两个主要威胁 所有老年人的独立性和生活质量。