Increased hypothalamic-pituitary-adrenal (HPA) axis activity in aging and AD may be a risk factor for the psychopathology of Alzheimer's disease (AD). This application proposes to continue to define mechanisms underlying increased HPA axis activity in AD. It also proposes to evaluate the ability of an antidepressant drug to reduce HPA axis responsiveness in AD and normal aging and to reduce the depressive signs and symptoms that frequently complicate AD. During the current funding period we have demonstrated in normal aging reduced sensitivity o the HPA axis to feedback inhibition by the endogenous glucocorticoid (GC) cortisol. Preliminary data suggest even further reduced sensitivity to GC feedback inhibition and increased basal HPA axis activity in early onset AD. The following Specific Aims will be pursued in groups of early onset AD, late onset AD, and normal old subjects: Specific Aim 1 will address the hypothesis that HPA axis sensitivity to GC feedback inhibition is reduced in early onset AD. The adrenocorticotropin (ACTH) response to a 150-minute exogenous cortisol infusion will be measured following removal of endogenous GC feedback by the cortisol synthesis inhibitor metyrapone. In addition, 24 hour urinary free cortisol and morning, afternoon and evening salivary cortisol will be measured to assess integrated HPA axis activity and cortisol diurnal rhythm. Specific Aim 2 will address the hypotheses that (a) the selective serotonin reuptake inhibitor antidepressant drug sertraline increases HPA axis sensitivity to GC feedback inhibition; and (b) sertraline reduces subsyndromal depressive signs and symptoms in AD. The proposed studies will determine the effects of a twelve-week course of sertraline or placebo on (a) HPA axis activity in all subjects (ACTH response to the metyrapone/cortisol protocol; 24 hour urinary free cortisol; morning, afternoon and evening salivary cortisols) and on (b) the presence and severity of depressive signs and symptoms in AD subjects. The results of the proposed studies will more clearly define mechanisms contributing to increased HPA axis activity in AD. Demonstrating increased HPA axis activity in early onset AD compared to late onset AD will provide supportive evidence that increased HPA axis activity is a risk factor for early expression of AD. The proposed studies also will evaluate the ability of an antidepressant to modify this potential risk factor for the expression of AD and provide a controlled treatment trial of a selective serotonin reuptake inhibitor for depressive signs and symptoms in AD.