Alzheimer’s Disease in Man and Transgenic Mice: Females at Higher Risk

Abstract

The major risk factors for Alzheimer’s disease (AD) are aging, Down’s syndrome, genetics, and a positive family history. Most, but not all, studies also find that aging women have a higher risk of developing AD than men. 1-4 Female apolipoprotein E4 (ApoE4) carriers are also at higher risk than males. 5-8 Together with the greater life expectancy of women in developed societies, this means that the majority of patients who live and die with AD are women. The etiology of the higher risk of AD in females is unknown. Perhaps because cognitive functions tend to be more distributed and bilateral in females compared to males, the neuronal disconnections associated with AD may affect women more profoundly. A role for estrogen, by influencing brain development (pre- or postmenarche) or senescence (postmenopause), is a leading hypothesis. In agreement with this notion, some studies suggest a protective effect of estrogen replacement therapy in the risk of developing AD. For example, the risk of developing AD among self-reported estrogen users is about one-third less than among non-users (odds ratio 0.65), and the risk decreases with increased duration and dosage of conjugated equine estrogen, the major form of estrogen replacement in clinical use. 9,10 Women who begin menstruation at later, rather than earlier, ages have a higher risk of developing AD. 9 A protective effect of estrogen is also found in a cohort of elderly women in Manhattan. In this study, estrogen use decreases the risk of developing AD by about half (odds ratios 0.40 and 0.50 after adjustment for education) and is independent of ApoE genotype. 11 Other studies, however, find no protective benefit of estrogen replacement therapy 12,13 and suggest that artifactual variables, such as higher socioeconomic status, more education, or better access to medical care among women who are prescribed estrogen, mediate this difference. A subsequent meta-analysis of ten studies, including eight case control and two prospective studies, found a risk reduction of 29% in postmenopausal women taking estrogen replacement therapy compared to untreated women. 14 Two more recent case-control studies also demonstrate a risk reduction of 58 to 72%. 15,16 Finally, a recent review of 15 case-control studies published since 1990 suggests that estrogen replacement decreases the risk of developing AD by half. 17 Given this epidemiological evidence, as well as positive results from brief, small, open trials of estrogen replacement in AD, 14 three large double-blind placebo-controlled clinical trials of patients with probable AD have now been published—all three with disappointing results. 18-20 With this information, estrogen replacement therapy cannot currently be recommended as a treatment for AD. Furthermore, the risk of developing AD should not factor into the difficult clinical and personal decision to use estrogen replacement, balancing its beneficial effects on osteoporosis, cardiovascular disease, and other conditions with its carcinogenic potential. The debate now centers on whether the gender effect of AD risk is in fact mediated by postmenopausal estrogen decline and, if so, whether treatment of patients diagnosed with probable AD is too little, too late. Perhaps estrogen must be given in preclinical stages of AD, such as in higher-risk subjects with isolated memory impairment or minimal cognitive impairment, as a preventive therapy. Testing of this hypothesis is underway in 5- and 10-year AD prevention trials, the results of which will be available in 2003 and 2008. Furthermore, the correct estrogen preparation, dosage, and duration, with or without progestins, route of administration (transcutaneous versus oral), and use of drug holidays may all influence the outcome of clinical trials.