Cognitive Vulnerability to Stress in Individuals at Risk for Alzheimer's Disease

项目总结/摘要 在阿尔茨海默病（AD）治疗试验的令人沮丧的结果之后，需要确定新的 方法是紧迫的。人们逐渐达成共识，认为AD临床试验缺乏疗效是由于 疾病的异质性。因此，确定可能成为AD的特定AD内表型的预测因子， 干预的目标非常重要。在可能的选择中，令人信服的证据表明， 作为一个有希望的候选人。事实上，许多研究的结果都表明， 对压力高度敏感的人患AD的风险更大，这表明这些人 个体可以代表可以在AD治疗试验中靶向的组。将这些发现转化为 然而，临床应用受到了阻碍，因为缺乏使用严格标准的研究之间的整合， 内分泌应激反应的实验研究和包括复杂的 患者样本的表征。我们的目标是解决这一关键差距。在本申请中，我们建议 进行一项前瞻性研究，以检查内分泌应激反应，负性 急性应激的认知影响，以及随后的认知下降，在60名男性和60名女性轻度 认知功能障碍（MCI）。对于我们的基本研究设计，我们将用特里尔诱发急性应激， 社会压力测试（TSST），然后测量内分泌激素和认知反应。的域 记忆和执行功能的变化将是主要的认知结果。收集的唾液样本 整个TSST的固定时间间隔将用于测量应激激素反应;皮质醇将是 主要激素结果。我们还将研究载脂蛋白E基因和多基因风险评分的影响， AD和收集与AD病理生理学相关的血液生物标志物。具体目标#1：确定 急性应激内分泌反应与记忆和执行测验成绩关系 在患有AD引起的MCI的个体中的急性应激之后。具体目标#2：检查 APOE基因型和多基因风险评分与急性应激内分泌反应和 AD所致MCI患者急性应激后的认知测试表现。具体目标#3： 在2年随访时确定认知能力下降和神经退行性变的预测因素。次要目标：行为 分别对男性和女性进行特定目标1-3的分析，以确定性别特异性预测因子 压力引起的认知障碍和认知能力下降以及神经退行性变的风险。 公共卫生意义：鉴于最近AD患者中许多降低淀粉样蛋白治疗的失败， 以确定新的潜在治疗机制。拟议的研究可以为未来的AD奠定基础 针对高危人群的压力脆弱性和HPA轴反应性的预防试验。

PROJECT SUMMARY/ABSTRACT In the wake of discouraging results from treatment trials in Alzheimer’s disease (AD), the need to identify novel approaches is urgent. There is emerging consensus that the lack of efficacy in AD clinical trials is attributable to disease heterogeneity. Accordingly, identifying predictors of specific AD endophenotypes that could become targets for intervention is of great interest. Among potential options, compelling evidence implicates the stress response as a promising candidate. Indeed, findings from numerous studies converge on the notion that individuals with a heightened sensitivity to stress are at greater risk of developing AD, suggesting that these individuals may represent a group who could be targeted in AD treatment trials. Translating these findings into clinical application has been hampered, however, by a lack of integration between studies that use rigorous experimental interrogation of the endocrine stress response and studies that include sophisticated characterization of patient samples. We aim to address this crucial gap. In this application, we propose to conduct a prospective study to examine the associations among the endocrine stress response, the negative cognitive effects of acute stress, and subsequent cognitive decline in 60 men and 60 women with mild cognitive impairment due to AD (MCI). For our basic study design, we will induce acute stress with the Trier Social Stress Test (TSST), and then measure the endocrine hormone and cognitive responses. The domains of memory and executive functioning will be the primary cognitive outcomes. Salivary samples collected at fixed intervals throughout the TSST will be used to measure stress hormone response; cortisol will be the primary hormone outcome. We will also examine the influence of the APOE gene and polygenic risk scores for AD and collect blood-based biomarkers associated with AD pathophysiology. Specific Aim #1: To determine the association between endocrine response to acute stress and memory and executive test performance following acute stress in individuals with MCI due to AD. Specific Aim #2: To examine the moderating effect of APOE genotype and polygenic risk score on the association between endocrine response to acute stress and cognitive test performance following acute stress in individuals with MCI due to AD. Specific Aim #3: To determine predictors of cognitive decline and neurodegeneration at 2-year follow-up. Secondary Aim: Conduct the analyses from Specific Aims 1-3 in men and women separately in order to identify sex-specific predictors of stress-induced cognitive impairment and cognitive decline and neurodegeneration after 2 years. Public health significance: Given the many recent failures of amyloid-lowering therapies in AD, it is important to identify new potential treatment mechanisms. The proposed study could lay the groundwork for future AD prevention trials targeting stress vulnerability and HPA-axis reactivity in at-risk individuals.