The experiences of elderly caregivers of Alzheimer relatives (CG) can be viewed as a model of chronic human stress in aging. Our work in the past funding cycle has been guided by the notion that such stress is accompanied by increased sympathoadrenalmedullary (SAM) activation whose cardiovascular and molecular responses may be amplified by superimposed stressors such as excessive care demands relative to respite received ("vulnerable CG"). The results to date indicate heightened basal circulating epinephrine (E) in vulnerable CG, altered L-selectin cell adhesion molecule (CAM) expression, down- regulation of beta-adrenergic receptors of lymphocytes, but no systematic changes in heart rate or blood pressure variability. Vulnerable CG who received a two week respite intervention demonstrated lessened circulating E in response to stressors compared to wait-listed CG, but there were no systematic treatment-related changes in other variables. Pilot data revealed: 1) increased expression of procoagulation factors (especially D-Dimer) which correlated with amount of sleep disturbance and level of catecholamines; 2) Vulnerable CG had less total sleep time and more awakenings than nonvulnerable CG. In the proposed research we wish to refine our understanding of the molecular changes underlying chronic and acute stress in elderly caregiving. The basic theory is that the chronic stress of caregiving yields a state of relative SAM arousal reflected in greater resting and stressor-related releases of catecholamines. As outcome variables of chronic and acute stressors related to caregiving, we shall focus on coagulation factors and cellular adhesion molecules, each of which has been associated with heightened risk of cardiovascular morbidity and mortality. The general hypothesis is that elderly caregivers, versus noncaregiving controls (NC) will have greater SAM arousal and greater expression of coagulation and adhesion molecules. It is posited further that those caregivers who have background medical risks (history of cardiovascular disease or hypertension), and who experienced superimposed stressors, such as excessive caregiving demands, or other negative life events, will be selectively vulnerable to these physiological changes. Disturbed sleep environment is posited to be one of the pathways whereby caregiving stressors are translated into SAM arousal and molecular changes. The study design calls for recruitment of 120 elderly caregivers (CG) and 60 noncaregiving controls (NC). Laboratory-derived speech stressor tasks will be used to probe differences in SAM responsivity to speech stressors between CG and NC, as well as CG at several levels of "mismatch" between caregiving demand and respite received. At-home polysomnography and actigraphy will monitor sleep disruption, sleep disorders (e.g., sleep apnea), and circadian activity variation. In the longitudinal phase, subjects will be re-evaluated annually to determine if hypothesized recovery of SAM arousability occurs in those CG who have placed their spouse, or whose spouse has died. The results of this research should bring us closer to understanding the physiological and molecular mechanisms underlying increased morbidity in elderly persons under chronic stress.