Contributions of stress reactivity to risk of Alzheimer's disease and related dementia's in a community-based cohort

Racial/ethnic minority adults are at higher risk for Alzheimer's disease and related dementias (ADRD). Moreover, minority adults are not only exposed to more intense and frequent stressful situations in their daily lives but they also have fewer resources to manage these situations in healthy ways. Limited resources among these adults may lead to impaired physiologic stress responses (i.e., stress reactivity), specifically dysregulation of the sympathetic nervous system and the hypothalamic-pituitary-adrenocortical (HPA) axis. Our understanding of the impact of stress reactivity on ADRD risk comes from animal studies and experiments in humans using controlled, laboratory stressors. This is a major limitation because laboratory stressors cannot capture the variety, severity, or duration of stressors that individuals face in their daily lives. Thus, there remains a need to more rigorously evaluate relationships of stress reactivity with ADRD risk in natural settings. We propose to fill this critical gap in the literature by adding more personalized and objective indicators of stress and stress reactivity to a longstanding community-based cohort, the Multi-Ethnic Study of Atherosclerosis (MESA). We will use existing gene expression data to calculate a molecular marker of the physiologic response to chronic exposure to adversity. We will also collect repeated measurements of stressful experiences, negative affect (emotions), and heart rate in order to develop participant-specific markers of affective and autonomic stress reactivity, respectively. Our overall goal is to use these measures to examine associations of the body's response to stressful experiences with risk of ADRD in a natural setting. We will leverage existing and ongoing repeated assessments of cognitive function as well as ongoing assessments of neuroimaging biomarkers of both vascular and AD pathology including cerebral blood flow (CBF), white matter hyperintensities, Aβ deposition, and gray matter volume loss. Our proposed study will allow us to begin to disentangle the pathways through which stress exposure and stress reactivity impact vascular dementia pathology and/or AD positivity. Findings will inform stress management interventions and precision medicine initiatives designed to prevent ADRD and/or slow its progression.