Few comparisons of the efficacy of different estrogenic formulations on brain function have been carried out. While most basic science studies have evaluated effects of estradiol, many of the clinical studies that have evaluated effects of hormone therapies (HT) in healthy older women have used conjugated equine estrogens (CEE). In this chapter, Gleason, Wharton, Carlsson, and Asthana review some of the cellular mechanisms by which estrogens are thought to protect the brain from age-related cognitive decline and Alzheimer's disease (AD), and discuss the pros and cons of oral vs. transdermal therapies and of estradiol vs. CEE. Their analysis identifies numerous advantages of transdermal estradiol vs. oral estrogenic therapies, primarily related to effects on liver enzymes, venus thromboembolic events, and inflammatory cytokines. Collectively, the analysis provides compelling arguments in favor of transdermal estradiol as the therapy of choice. Nevertheless, it is clear that the benefits of estradiol vs. CEE have yet to be proven, as has the efficacy of estrogenic therapies (ET) in the prevention of AD. These issues will be addressed in the recently initiated Kronos Early Estrogen Prevention Study (KEEPS) trial and the ancillary KEEPS study of cognitive aging. Details of the trial including its design and primary goals are discussed.