Neurodegeneration in Women

Alzheimer's disease (AD) is a progressive brain disease that results in a dementia accompanied by severe changes in cognitive ability, perception, and mood. Although the precise cause of the disease remains elusive, clusters of specific genetic factors (such as gender and expression of the apolipoprotein E [ApoE] gene) and environmental factors (such as smoking and alcohol use) can alter the risk of AD. Women appear to be at an increased risk for AD, although women's longer life spans may contribute to this differential risk. Specifically, the loss of hormones at menopause has emerged as a significant risk factor for AD (Tang et al. 1996; Kawas et al. 1997). With an average life span of 78 years and typical menopausal onset between 48 and 54 years, women spend a significant portion of their lives in an estrogen-deprived state. Because hormonal changes that accompany menopause increase vasomotor dysfunction, hormone replacement therapy has frequently been recommended to symptomatic women. Epidemiological studies of this population, reviewed below, indicate that estrogen replacement at menopause may decrease the risk of neurodegenerative diseases such as AD. This sidebar also examines experimental research designed to determine whether females are more vulnerable than males to alcohol-induced neurocognitive effects. Estrogen and Risk for AD Research shows that estrogen therapy in surgically menopausal women (i.e., women who have experienced induced menopause caused by surgical removal of both ovaries) (Sherwin 1988) and in women receiving therapy to suppress ovarian function (Sherwin and Tulandi 1996) improves cognitive functions such as concentration and attention span. These findings suggest that estrogen may have a protective role in neurodegenerative diseases such as AD. On the other hand, studies that correlated prior estrogen usage with the incidence of AD have reported mixed findings-some reporting that estrogen is beneficial, others finding that estrogen is detrimental (reviewed in Henderson 1997). As with any retrospective study, data regarding hormone usage were frequently obtained from caregivers and secondary sources, which may not accurately reflect estrogen usage by the patient. More consistent data have been obtained from prospective studies, for which women were followed for several years to determine the effects of estrogen replacement. Results from two recent prospective studies (Tang et al. 1996; Kawas et al. 1997) found that estrogen replacement starting before menopause (i.e., during perimenopause) significantly decreased the risk of AD. Estrogen therapy does not appear to be beneficial for women with AD, however. Although initial short-term trials with small sample sizes suggested that estrogen replacement was beneficial in female AD patients (Fillit et al. 1986; Honjo et al. 1989), subsequent studies with larger patient populations failed to confirm these findings (Henderson et al. 2000). A recent large-scale, multicenter trial involving female patients with moderate AD reported a modest improvement among patients after 2 months of estrogen replacement but no improvement at 12 months of treatment. Test scores worsened on some measures (Mulnard et al. 2000). These data as well as those from a recent study of cognitively intact postmenopausal women (Drake et al. 2000) underscore the fact that estrogen's effects on cognition are likely to be complex. Although the prospective studies and the clinical studies diverge in their conclusions about estrogen's efficacy, it should be noted that the populations studied in each case are different. Women in the clinical studies were already exhibiting AD symptoms when they entered the study and were therefore likely to have had significant neural damage. Estrogen replacement may therefore be ineffective when hormone-sensitive neurons are lost. Furthermore, the re-introduction of estrogen after a prolonged period of hormone deprivation (approximately 20 years in some studies) may not be an effective replacement strategy. …