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

认知能力下降超过与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)。ADRD中观察到的认知能力下降反映了大脑的潜在变化 形态学。最近，阿尔茨海默病研究人员发现了阿尔茨海默病的一种皮质疾病特征，它与 AD患者的症状严重程度，并前瞻性地预测认知正常的成年人中AD的发展。 因此，认知功能低下和脑形态异常可能是未来ADRD风险的指标。 配偶丧亲等应激性生活事件会显著增加认知功能减退和ADRD的发生率 寡妇(呃)S。然而，关于配偶丧亲如何增加ADRD风险的了解有限 而哪个寡妇(呃)S面临的风险最大。压力相关机制可能导致认知障碍 寡妇(呃)S的结局和ADRD风险增加。例如，抑郁症状和全身炎症 长期暴露在压力之下的情况也与认知功能低下有关。 以及AD相关区域的神经退行性变。尽管研究表明寡妇(呃)S表现出更高的 抑郁症状的水平和免疫功能的不适应模式比没有失去亲人的成年人，没有工作 同时研究了与压力相关的身心健康变化与认知能力之间的关系 寡妇(呃)S中AD的功能和神经影像生物标志物。为此，本研究探索 抑郁症状、全身炎症、认知功能和精神障碍之间的关系 寡妇(呃)S的阿尔茨海默病的皮质疾病征象。具体目的：(1)表征 抑郁症状、AD皮质特征和认知功能(2)来表征两者之间的关系 抑郁症状、炎症和AD皮质征象(探索性)之间的关系 抑郁症状、基于血液的磷酸化tau和AD皮质特征之间的关系。 假设：(H1a)抑郁症状与认知功能呈负相关。(H1B)稀释剂 AD区皮质强化抑郁症状与认知功能的负相关 功能。(H2)更高的炎症水平会加强抑郁症之间的负面关系 阿尔茨海默病患者的症状和皮质厚度。研究设计：在R21父母资助范围内，80名寡妇(呃)S 将接受结构性核磁共振扫描，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系统性红斑狼疮的标志物 炎症(即IL-6、TNF-α、IL-1b)和tau。AD皮质签名将通过应用基于atlas的 分割方法分离先验AD感兴趣区的皮质厚度。这项研究将加强 认知障碍和阿尔茨海默病神经生物学风险相关的生物心理社会机制的知识， 改进对高危个人的早期识别，并为制定量身定制的干预措施提供信息， 延迟或减少ADRD的发病。

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.