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

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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.