Wharton, Asthana, and Gleason review trials that have evaluated the efficacy of estrogenic therapies in the treatment and prevention of Alzheimer's disease (AD). They point out that of three large clinical trials that used conjugated equine estrogen (CEE) therapies, all reported no cognitive benefits in women with AD. This is in contrast to several small observational and uncontrolled studies that reported positive effects of estrogens on measures of mood, memory, and dementia, as well as two more recent observational trials in which long-term treatment with estradiol appeared to protect ‘at-risk’ women from AD-related pathologies (hippocampal atrophy and neuronal metabolism). In addition, two recent controlled trials evaluated the effects of transdermal estradiol on cognitive function in women with AD. These trials demonstrated rapid improvement in verbal memory, which correlated positively with plasma estradiol levels, in addition to positive effects on attention, visual memory, and semantic memory. The authors' analysis highlights the need for more research on the pharmacology of estrogenic effects on cognitive function, and in particular on the benefits of transdermal estradiol vs. oral CEE-based therapies in women with AD.

Testosterone, an androgen, is viewed as a male hormone and for this reason is less studied in women than in men. In postmenopausal women, testosterone concentrations are affected by a number of factors, including age and whether a woman has undergone oophorectomy. Past hormonal exposures may also be relevant. In this chapter, Wharton, Asthana, and Gleason review research indicating that testosterone affects function of the hippocampus and other brain regions, and that testosterone has actions that might be expected to reduce Alzheimer's disease (AD) risk in women as well as men. Some studies in women suggest a relation between testosterone therapy or testosterone concentrations and performance on cognitive tasks involving visuospatial abilities. Unfortunately, few data are available on testosterone administration in women at risk for AD or with symptoms of this disorder. The authors conclude that further research is warranted on the cognitive effects of testosterone administration in older women, perhaps concurrently with estradiol and perhaps particularly in women who have experienced surgical menopause.

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.