DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disorder that results in the insidious onset and gradual progression of deficits in memory and other cognitive and functional abilities. The neuropathologic changes associated with AD begin in the hippocampus and surrounding areas, brain regions known to be crucial for memory. Recent conceptualizations of AD suggest that these changes begin well before clinical symptoms become apparent, and that the onset of symptoms and their progression may be influenced by any comorbid factor that increases neuronal vulnerability in these regions. One potential comorbid factor is chronic psychological stress. Numerous studies have shown that chronic stress results in the release of glucocorticoids that target the brain and exert their actions primarily on the hippocampus, with consequent loss of neurons and synapses and decline in memory. This suggests that comorbid, prolonged stress will adversely affect the integrity of mesial temporal structures and, as a result, will hasten the development of the dementia syndrome that characterizes AD in individuals who are likely to be in a preclinical phase. One such group, those with Mild Cognitive Impairment (MCI), have been identified as having memory complaints, mild memory loss on objective psychometric testing, and little or no loss of other cognitive functions or skills in activities of daily living. The present project will compare older, normal control and MCI subjects on measures of baseline psychological and physiological (cortisol) stress, with attention to the reactions of MCI subjects to potentially stressful events and difficulties, including loss of memory. Taking into account other risk factors for AD (e.g., age, APOE status), the project will determine the degree to which psychological and physiological stress sustained over time, increase susceptibility to cognitive decline, particularly memory loss, and conversion to clinically apparent AD, in subjects with MCI. If memory decline and the development of dementia are exacerbated by chronic stress in individuals with preclinical AD, behavioral and/or psychopharmacological means of ameliorating stress could delay the onset of clinical symptoms of AD by months or even years.