Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled trial.

BACKGROUND: AD, the most prevalent cause of dementia, affects twice as many women as men. Therapeutic options are limited, but results of prior studies support the hypothesis that estrogen treatment may improve symptoms of women with this disorder. METHODS: Forty-two women with mild-to-moderate dementia due to AD were enrolled into a randomized, double-blind, placebo-controlled, parallel-group trial of unopposed conjugated equine estrogens (1.25 mg/day) for 16 weeks. RESULTS: Outcome data were available for 40 women at 4 weeks and 36 women at 16 weeks. At both 4 and 16 weeks, there were no significant differences or statistical trends between treatment groups on the primary outcome measure (the cognitive subscale of the Alzheimer's Disease Assessment Scale), clinician-rated global impression of change, or caregiver-rated functional status. Exploratory analyses of mood and specific aspects of cognitive performance also failed to demonstrate substantial group differences. CONCLUSION: Although conclusions are limited by small sample size and the possibility of a type II error, results suggest that short-term estrogen therapy does not improve symptoms of most women with AD. These findings do not address possible long-term effects of estrogen in AD, possible interactions between estrogen and other treatment modalities, or putative effects of estrogen in preventing or delaying onset of this disorder.

Associations between circulating sex steroid hormones and cognition in normal elderly women.

OBJECTIVE: To provide exploratory analyses of associations between levels of several sex hormones and cognitive performance in elderly women. BACKGROUND: Sex steroid hormones are implicated in the cognitive processes of the adult brain. Comparing cognitive performance across or between conditions associated with different hormone levels, such as phases of the menstrual cycle, surgical menopause, and estrogen replacement therapy suggests conditions with higher levels of estrogen are associated with better verbal memory and possibly worse visuospatial ability. METHOD: The authors measured circulating sex hormone levels in 39 highly educated, nondemented, predominantly white elderly women. Levels were correlated with neuropsychological performance, controlling for age, education, frequency of prior testing, use of estrogen replacement, and depression. RESULTS: High estradiol levels were associated with better delayed verbal memory and retrieval efficiency, whereas low levels were associated with better immediate and delayed visual memory. Levels of testosterone were related positively to verbal fluency. Levels of progesterone and androstenedione were unrelated to cognitive performance. CONCLUSIONS: Both estrogen and testosterone showed associations with cognitive performance. Estrogen may enhance, and depress, specific cognitive skills.

Pregnancy, the postpartum, and steroid hormones: effects on cognition and mood.

The effects of pregnancy on cognition and mood were examined using a repeated-measures design. Nineteen women, average age 33, were tested with a comprehensive neuropsychological battery during their last 2 months of pregnancy and again within 2 months of delivery. Blood samples were obtained from all subjects and assayed for a variety of steroid hormones implicated in cognitive and mood functioning. Most participants also completed several self-report measures of mood. In comparison with performance after delivery, women showed significantly more impairment in aspects of verbal memory during pregnancy and also tended to report more negative mood states. Memory deficits were not explained by mood disturbances. No hormone assayed consistently related to cognitive performance during pregnancy. During pregnancy, higher levels of progesterone (P) were associated with greater mood disturbances and higher levels of dehydroepiandrosterone (DHEA) with better mood. After delivery, testosterone (T) was strongly and consistently associated with greater reported mood disturbances. Our results confirm a peripartal memory deficit, which cannot be explained by the dramatic rise in circulating steroid hormones, or by mood status during pregnancy. Steroidal hormones, namely P, DHEA and T, appear to play a role in mood disturbances during, and after, pregnancy. Studies beginning earlier in pregnancy and continuing for an extended period of time after delivery are needed to confirm and expand these observations.

Long-term soy isoflavone supplementation and cognition in women: a randomized, controlled trial.

OBJECTIVE: To determine the cognitive effects of long-term dietary soy isoflavones in a daily dose comparable to that of traditional Asian diets. METHODS: In the double-blind Women's Isoflavone Soy Health trial, healthy postmenopausal women were randomly allocated to receive daily 25 g of isoflavone-rich soy protein (91 mg of aglycone weight of isoflavones: 52 mg of genistein, 36 mg of daidzein, and 3 mg glycitein) or milk protein-matched placebo. The primary cognitive endpoint compared between groups at 2.5 years was change from baseline on global cognition, a composite of the weighted sum of 14 neuropsychological test score changes. Secondary outcomes compared changes in cognitive factors and individual tests. RESULTS: A total of 350 healthy postmenopausal women aged 45-92 years enrolled in this trial; 313 women with baseline and endpoint cognitive test data were included in intention-to-treat analyses. Adherence in both groups was nearly 90%. There was no significant between-group difference on change from baseline in global cognition (mean standardized improvement of 0.42 in the isoflavone group and 0.31 in the placebo group; mean standardized difference 0.11, 95% confidence interval [CI] -0.13 to 0.35). Secondary analyses indicated greater improvement on a visual memory factor in the isoflavone group (mean standardized difference 0.33, 95% CI 0.06-0.60) but no significant between-group differences on 3 other cognitive factors or individual test scores, and no significant difference within a subgroup of younger postmenopausal women. CONCLUSION: For healthy postmenopausal women, long-term dietary soy isoflavone supplementation in a dose comparable to that of traditional Asian diets has no effect on global cognition but may improve visual memory. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that long-term dietary supplementation with isoflavone-rich soy protein does not improve global cognition of healthy postmenopausal women.

Anosognosia and Alzheimer's disease: the role of depressive symptoms in mediating impaired insight.

The relation between anosognosia and dementia severity in Alzheimer's disease (AD) has been unclear. We constructed a measure that quantified the difference between the perceptions of deficits of patients with AD (n = 23) and ratings from a knowledgeable informant as a measure of anosognosia. There was no correlation between dementia severity and anosognosia. However, dementia severity was positively correlated with the degree of anosognosia after controlling for depressive symptomatology (p =.03). Post-hoc analyses, also controlling for depressive symptoms, indicated that higher levels of anosognosia were associated with lower performance on specific cognitive tasks. These results suggest depressive symptoms may confound the relationship between anosognosia and dementia severity.

Lifelong estrogen exposure and cognitive performance in elderly women.

Fluctuating endogenous and exogenous estrogens influence cognition in women. In this study, cognitive functioning in elderly women was examined by applying methodology used in understanding the effects of chronic estrogen exposure on hormone-sensitive tissue other than the brain. An index, combining menstrual, reproductive, and physical markers associated with estrogen levels, was developed for elderly, nondemented, predominantly Caucasian women (n = 87). This index related to better performance on two verbal factors, one attentional and one global in nature. Findings suggest that estrogen exposure across the life span plays a role in brain aging. Possible physiological mechanisms for this effect are discussed.