07 Dec 2001

Dr. Samuel Gandy of Thomas Jefferson Medical School began his presentation by stating that since 1990, 14 of 15 epidemiological studies reported that hormone replacement therapy (HRT) reduced the relative risk of AD in postmenopausal women by about 50 percent. Dr. Gandy and coworkers hypothesized that HRT might modulate AD risk through hormonal control of Aβ metabolism, and they have tested this hypothesis by examining the effect of ovariectomy on Aβ levels in the brains of experimental animals and in the circulation of elderly men with prostate cancer treated with antigonadal therapy. Notably, compared to controls, brain levels of Aβ40 and 42 were increased 150 percent in guinea pigs subjected to ovariectomy, but brain levels of Aβ returned nearly to control values when the ovariectomized guinea pigs were treated orally with one or five mg/kg/day 17β-estradiol. Dr. Gandy and colleagues then extended these studies to a model of the human clinical situation by examining six men who were undergoing therapeutic androgen suppression therapy for treatment of prostate cancer, and they reported that plasma levels of β-amyloid doubled in association with declining levels of circulating testosterone and estrogen. Further, the elevated plasma Aβ levels persisted for at least the first six months of therapy. Thus, these data suggest that gonadal hormones play a key role in controlling Aβ levels in vivo in experimental animals and in humans, and, despite the lack of efficacy in treating advanced AD with HRT in recent clinical trials using estrogens, it is possible that earlier HRT intervention in individuals with mild cognitive impairment, a prodromal phase of AD, or even in early AD, may be effective in slowing disease progression.—John Trojanowski