DESCRIPTION (provided by applicant): The last several years have seen an explosion of studies showing relationships between cognitive performance and sex steroid supplementation in men and women. These studies are most notable for their implications for cognitive aging and because they raise the possibility of protection against age-related neurologic diseases or age-related cognitive decline. The mechanism(s) that underlie the cognitive effects of sex steroids in humans are unknown. The overall goal of this research program is to initiate studies of the metabolic pathways that underlie the cognitive effects of sex steroids in human aging. Therefore, we will examine which androgen pathway underlies cognitive effects of androgen supplementation in men (Aim 1) by comparing cognitive performance before and after manipulation of sex steroids. We will administer a gonadotropin releasing hormone agonist, and simultaneously replaced with testosterone (T), T+ an aromatase inhibitor (preventing T's conversion to estradiol (E2)), or a placebo in a double blind manner in both younger and older men. We will examine whether T has cognitive effects in older women and the pathway of these effects by testing cognition in older women before and after T, T+aromatase inhibitor, E2 alone, or no replacement (Aim 2). This research program utilizes a cognitive neuroscience framework such that the critical brain systems for each cognitive domain (working memory, perception, verbal and nonverbal memory, motor sequence learning) have been delineated in previous studies. The tasks are those that particularly decline in aging, and have shown sex differences and/or sex steroid effects in previous studies. Findings that cognitive effects are due to aromatization to E2 in men versus action at T receptors, and findings that T affects cognition in women would give significant direction to the creation of tissue specific, sex steroid-related pharmacologic treatments for brain aging.