Advancing age is the most significant risk factor for the development of Alzheimer's disease (AD). Men, like women, experience a robust decline in circulating levels of their primary sex steroid hormones, testosterone (T) and its active metabolite dihydrotestosterone (DHT), as a consequence of normal aging. In men, decreases in testosterone leads to functional impairments in androgen-responsive tissues such as bone, muscle, heart, and brain that are often manifested as the clinical syndrome 'androgen deficiency in aging males'. As an androgen-responsive tissue, the brain may also be vulnerable to normal age-related reductions in T and DHT. Recent studies have shown that androgens are neuroprotective and regulate levels (?-amyloid (A?) protein. The goal of proposal is to determine if normal age-related androgen depletion will impair the beneficial actions of androgens, thereby increasing the vulnerability of the aging male brain to the development of AD pathology. The proposed studies will utilize a combination of animal models and analyses of human tissues to investigate the hypothesis that age-related androgen depletion increases the risk for developing AD. ? ?
