The Role of Estrogen in the Development of Age-Related Cognitive Impairment and Dementia

Special Report: Neuropsychiatry

During and after menopause, many women report impairments in cognitive functioning. One of the most controversial issues in medicine today is the decision to prescribe hormone therapy for women as a way to mitigate the physical and cognitive symptoms of menopause. There is some evidence that estrogen therapy (ET) results in the maintenance of a premenopausal level of cognitive functioning^1-4 and may reduce the risk of Alzheimer disease (AD).^5-8 With many in the baby boom generation now well into menopause, this issue will be of increasing importance in the coming years.

Studies examining the difference in hormone levels in postmenopausal women with and without AD yield contrasting results. While one study found women with AD to have significantly lower estradiol(Drug information on estradiol) levels than healthy controls,⁹ suggesting a possible relationship between estrogen and the risk of AD, another study found no significant difference in estradiol levels between these 2 groups and no correlation between cognitive performance and hormone levels.¹⁰

Women appear to be at higher risk for AD than men, particularly if they carry the APOE4 allele.¹¹ Furthermore, certain estrogen receptor 1 polymorphisms appear to be associated with the risk of cognitive impairment.¹² Estrogen reduces neuronal generation of β-amyloid peptides, which may cause a delay in the onset of AD.¹³

There is considerable epidemiologic evidence from both prospective and case-control studies that estrogen use in postmenopausal women may decrease the risk of the development and/or expression of AD,^5-8,14,15 with an overall odds ratio of 0.66,16 but not all studies have found this.¹⁷ ET alone may improve cognitive functioning in female AD patients.¹⁸ However, other trials of estrogen alone as a therapy for mild to moderate AD have had equivocal results, showing no significant effect on cognitive measures of long-term progression,^19-21 suggesting that estrogen alone cannot significantly prevent progression of an already established disease.

ET may, however, be helpful in cognitive decline resulting from normal aging, as opposed to reversing or preventing established AD pathology specifically. Some of the most consistent evidence for a direct effect of estrogen on cognitive function is from studies of surgically menopausal women.

Sherwin²² studied women after total abdominal hysterectomy/bilateral salpingo-oophorectomy with random assignment to estrogen or placebo for 3 months and found that the treated group showed preservation of verbal memory, while the placebo group showed a significant decline. These data were confirmed in a study showing that, for 3 months after this surgery, estrogen- treated women showed either improvement in or preservation of verbal learning and memory performance, while placebo-treated women showed a decline.²³

In a naturalistic study, women who received estrogen after surgical menopause had better preserved verbal memory and constructional ability than women not receiving estrogen.²⁴ In addition, 2 studies showed that ET specifically improves attentional functions, compared with placebo treatment.^4,25