Cognitive and neuroendocrine response to transdermal estrogen in postmenopausal women with Alzheimer's disease: results of a placebo-controlled, double-blind, pilot study

Preliminary evidence from clinical studies indicates that treatment with es trogen augments cognitive function for women with Alzheimer's disease (AD). The neurobiology of estrogen, particularly its neuromodulatory and neuropr otective actions, provide a viable basis to support such cognition-enhancin g effects, We conducted a placebo-controlled, double-blind, parallel-group design pilot clinical study to evaluate the cognitive and neuroendocrine re sponse to estrogen administration for postmenopausal women with AD. Twelve women with probable AD of mild-moderate severity completed the study. Durin g an eight week treatment period, six women received 0.05 mg/day dosage of 17 beta-estradiol via a skin patch and the remaining six wore a placebo ski n patch. Subjects were randomized to equal distribution, and evaluated at b aseline, at weeks 1, 3, 5, and 8 on treatment, and at weeks 9, 10, 11, and 13 off treatment. On each day of evaluation, cognition was assessed using a battery of neuropsychological tests, and blood samples were collected to m easure plasma concentrations of estradiol and estrone. In addition, several neuroendocrine markers were measured in plasma to evaluate the relationshi p between estrogen-induced cognitive effects and fluctuations in the catech olaminergic and insulin-like growth factor systems. Significant effects of estrogen treatment were observed on attention (i.e. Stroop: number of self- corrections in the Interference condition, F[1,8] = 8.22, P < 0.03) and ver bal memory (i.e., Buschke: delayed cued recall, F[3,30] = 4.31, P < 0.02). The salutary effects of estrogen on cognition were observed after the first week of treatment, and started to diminish when treatment was terminated. For women treated with estrogen, enhancement in verbal memory was positivel y correlated with plasma levels of estradiol (r = 0.96, P < 0.02) and negat ively correlated with concentrations of insulin-like growth factor binding protein-3 (IGFBP-3) in plasma (r = -0.92, P < 0.03). Furthermore, a trend i n the data was evident to suggest a negative relationship between plasma le vels of insulin-like growth factor-1 (IGF-1) and verbal memory (r = -0.86, P = 0.06). Estrogen administration suppressed peripheral markers of the IGF system, as evidenced by a negative correlation between plasma concentratio n of estradiol and IGF-1 (r = -0.93, P < 0.03), and a trend for a similar r elationship between plasma levels of estradiol and IGFBP-3 (r = - 0.86, P = 0.06). With respect to the catecholamines assayed, norepinephrine was posi tively correlated with verbal memory (r = 0.95, P < 0.02) for women who wer e treated with estrogen. Furthermore, there was a trend to suggest a negati ve relationship between plasma epinephrine levels and the number of errors committed on a test of attention (r = -0.84, P = 0.07). In the placebo grou p, no significant effects of estrogen replacement were evident either on me asures of cognition or on any of the neuroendocrine markers. The results of this study suggest that estrogen replacement may enhance cognition for pos tmenopausal women with AD. Furthermore, several markers of neuroendocrine a ctivity may serve to index the magnitude of estrogen-induced facilitation o n cognition. In addition, research findings from the present study will pro vide important information for the design of larger prospective clinical st udies that are essential to definitively establish the therapeutic role of estrogen replacement for postmenopausal women with AD. Published by Elsevie r Science Ltd.