application) The proposed program builds on the applicant's previous experience in the area of spatial memory, aging and Alzheimer's disease (AD) and extends these skills in the neurosciences by examining hormone effects on spatial memory in aging and AD. The proposed research training program will provide the applicant with unique inter- disciplinary training and additional skills in neuro-endocrinology. This additional training will enable the applicant to achieve independence and prominence as an academic researcher with unique multi-disciplinary skills critical for the study of complex diseases such as Alzheimer's disease. In the proposed research study, the applicant will examine the relationship between gonadal hormones on cognition in healthy older men and Alzheimer's disease (AD). Testosterone (T) has been demonstrated to have a number of effects on behavior in both animals and humans, and in particular has been shown to improve spatial abilities and spatial memory. The effects are presumably mediated through the androgen receptor which is widely, but selectively distributed throughout the brain. The hippocampus and medial temporal regions, which underlie certain spatial abilities such as spatial memory, are a particular target for gonadal hormones and demonstrate neural growth in response to androgen release. These same brain regions are affected in AD, for which impaired memory and spatial disorientation are hallmark symptoms. Testosterone administration to normal older men has been reported to improve spatial abilities, although another investigation failed to find similar effects. Several explanations have been proposed to account for these inconsistent findings. First, like many hormonal effects on cognition, it is possible that T effects occur within an optimal dose range. Second, T is aromatized in vivo to estradiol, a gonadal hormone that may affect cognition. Previous studies have not addressed how the aromatization of T to estradiol may contribute to changes in cognition or how increasing T to levels of healthy young men effect cognition. The applicant's proposed program will address these questions through a series of studies. Study 1 will examine the effects of three doses of T (low, medium, high) on cognition in healthy older men, and will determine T effects when estradiol is suppressed using an aromatase inhibitor. Study 2 will examine the effects of T administration on cognition in patients with Alzheimer's disease (AD).
