From stress to dementia risk: An examination of psychological, immunological, and neurobiological mechanisms underlying increased risk for Alzheimer’s disease and related dementias in widow(er)s

认知能力下降超过年龄相关的认知能力下降是阿尔茨海默病（AD）的危险因素 和相关痴呆症（ADRD）。在ADRD中观察到的认知下降反映了大脑的潜在变化， 形态学最近，AD研究人员已经确定了AD的皮质疾病特征， AD患者的症状严重程度，并前瞻性预测认知正常成人的AD发展。 因此，认知功能差和脑形态异常可能是未来ADRD风险的指标。 压力性生活事件，如配偶丧亲，显着增加认知能力下降和ADRD的发生率， 寡妇的然而，对配偶丧亲之痛如何增加ADRD风险的理解有限 哪些寡妇风险最大。与压力相关的机制可能会导致认知能力差 结果和寡妇ADRD风险升高。例如，抑郁症状和全身炎症 - 长期暴露于压力之后的状况-也与认知功能低下有关 和AD相关区域的神经变性。尽管有研究表明寡妇（鳏夫）表现出更高的 抑郁症状水平和免疫功能的适应不良模式比非丧亲成年人，没有工作 同时研究了与压力相关的生理和心理健康变化与认知能力的关系。 寡妇（鳏夫）中AD的功能和神经影像学标志物。为此，本研究探讨了 抑郁症状、全身性炎症、认知功能和 寡妇中AD的皮质疾病特征。具体目标：（1）确定 抑郁症状、AD皮质特征和认知功能（2）描述 抑郁症状、炎症和AD皮质信号之间的关系（探索性） 抑郁症状、血液磷酸化tau蛋白和AD皮质信号之间的关系。 假设：（H1 a）抑郁症状与认知功能呈负相关。(H1b)薄 AD脑区的皮层会加强抑郁症状与认知功能之间的负相关关系 功能(H2)更高水平的炎症会加强抑郁症与抑郁症之间的负面关系。 症状和AD区域的皮质厚度。研究设计：在R21父母补助金资助范围内，80名寡妇（或鳏夫） 将接受结构MRI扫描，接受静脉抽血，进行认知评估，并自我报告 配偶死亡后6个月出现抑郁症状。血液分析将用于评估全身性 炎症（即，IL-6、TNF-α、IL-1b）和tau。AD皮质特征将通过应用基于图谱的 分割方法，以隔离感兴趣的先验AD区域中的皮质厚度。这项研究将提高 认知障碍和AD神经生物学风险相关的生物心理社会机制的知识， 改善对高危人群的早期识别，并为制定量身定制的干预措施提供信息， 延迟或减少ADRD发作。

Cognitive decline that exceeds age-related decreases in cognition is a risk factor for Alzheimer’s disease (AD) and related dementias (ADRD). The cognitive decline observed in ADRD reflects underlying changes in brain morphology. Recently, AD researchers have identified a cortical disease signature of AD that correlates with symptom severity in AD patients and prospectively predicts the development of AD in cognitively normal adults. Hence, poor cognitive function and abnormal brain morphology may serve as indicators of future ADRD risk. Stressful life events such as spousal bereavement significantly increase rates of cognitive decline and ADRD in widow(er)s. However, there is limited understanding of how spousal bereavement increases ADRD risk and which widow(er)s are at greatest risk. Stress-related mechanisms likely contribute to poor cognitive outcomes and elevated ADRD risk in widow(er)s. For example, depressive symptoms and systemic inflammation – conditions that often follow prolonged exposures to stress – are also associated with poor cognitive function and neurodegeneration in AD-related regions. Despite studies demonstrating that widow(er)s exhibit higher levels of depressive symptoms and maladaptive patterns of immune function than nonbereaved adults, no work has simultaneously examined how stress-related changes in physical and mental health relate to cognitive function and neuroimaging biomarkers of AD among widow(er)s. Toward this end, the current study explores the relationships between depressive symptoms, systemic inflammation, cognitive function, and the cortical disease signature of AD in widow(er)s. Specific aims: (1) To characterize the relationship between depressive symptoms, the AD cortical signature, and cognitive function (2) To characterize the relationship between depressive symptoms, inflammation, and the AD cortical signature (Exploratory) To examine relationships between depressive symptoms, blood-based phosphorylated tau, and the AD cortical signature. Hypotheses: (H1a) Depressive symptoms will be negatively associated with cognitive function. (H1b) Thinner cortex in AD regions will strengthen the negative relationship between depressive symptoms and cognitive function. (H2) Higher levels of inflammation will strengthen the negative relationship between depressive symptoms and cortical thickness in AD regions. Study design: Within a funded R21 parent grant, 80 widow(er)s will undergo a structural MRI scan, receive a venous blood draw, perform cognitive assessments, and self-report depressive symptoms at 6 months post-spousal death. Blood assays will be used to assess markers of systemic inflammation (i.e., IL-6, TNF-a, IL-1b) and tau. The AD cortical signature will be obtained by applying atlas-based parcellation methods to isolate cortical thickness in a priori AD regions of interest. This study will enhance knowledge of biopsychosocial mechanisms related to cognitive impairment and neurobiological risk for AD, improve early identification of at-risk individuals, and inform the development of tailored interventions that may delay or reduce ADRD onset.