2005- Update: Raloxifene (actually for prevention of osteoporosis) and other selective estrogen receptor modulators might be useful for prevention of Alzheimer's. Kristine Yaffe's work at the San Francisco VA Medical Center is the most interesting.

Estrogen Replacement Therapy

Recent findings about estrogens (2/5/02, Journal of the American Medical Association) suggests some caution is advised concerning the use of estrogen replacement therapy for cognitive or emotional problems. The latest findings about the relaltionship between estrogen levels and cognitive functioning indicate "no association between hormone levels and cognitive functioning after either 2 or 12 months of treatment" (Leon Thal et al, Archives of Neurology, Volume 60, pages 209-212, February, 2003).
Other recent findings about high dose estrogen (e.g. 11/02, Journal of the American Medical Association) seem positive. However, previous years' results about estrogen use for memory loss prevention/treatment were mostly negative. Recent animal model experiments on estrogen attenuation of beta-amyloid peptide have not been encouraging (2/24/05, PS Green et al, Endocrinology).

One problem with the studies indicating that estrogens lower the risk of AD is that women are never randomly assigned to get estrogens or a placebo in a controlled study. This can be taken into account, but there is always the possibility that the women who take estrogens were less likely to get Alzheimer's to begin with. The latest good prospective analysis of risk factors for Alzheimer's disease (Lindsay J, Laurin D, Verreault R, Hebert R, Helliwell B, Hill GB, McDowell I. Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol;156(5):445-53, 2002) found no relationship between estrogens and risk of AD. Even if estrogens have a protective effect, it looks like a small effect requires a decade or more of consistent use (JAMA, November, 2002, JC Breitner et al).

Positive results: High-dose estradiol improves cognition for women with AD: Results of a randomized study.
Asthana S, Baker LD, Craft S, Stanczyk FZ, Veith RC, Raskind MA, Plymate SR.

OBJECTIVE: To characterize the cognitive and neuroendocrine response to treatment with a high dose of estrogen for postmenopausal women with AD.

METHODS: Twenty postmenopausal women with AD were randomized to receive either 0.10 mg/day of 17beta-estradiol by skin patch or a placebo patch for 8 weeks. Subjects were evaluated at baseline, at weeks 3, 5, and 8 during treatment, and again 8 weeks after treatment termination. During each visit, cognition was assessed with a battery of neuropsychological tests, and blood samples were collected to measure plasma estradiol as well as several other neuroendocrine markers of interest.

RESULTS: Significant effects of estrogen treatment were observed on attention (Stroop Color Word Interference Test), verbal memory (Buschke Selective Reminding Test), and visual memory (Figure Copy/Memory). In addition, women treated with estrogen demonstrated improved performance on a test of semantic memory (Boston Naming Test) compared with subjects who received a placebo. Estrogen appeared to have a suppressive effect on the insulin-like growth factor (IGF) system such that plasma concentration of IGF binding protein-3 was significantly reduced and plasma levels of estradiol and IGF-I were negatively correlated during estrogen treatment.

CONCLUSIONS: Administration of a higher dose of estrogen may enhance attention and memory for postmenopausal women with AD. Although these findings provide further clinical evidence to support a cognitive benefit of estrogen for women with AD, studies evaluating the effect of estradiol administration, in particular, using larger sample sizes and for longer treatment durations are warranted before the therapeutic potential of estrogen replacement for women with AD can be firmly established.

Our Comment about this study: One concern about this research is that significant effects were obtained on just a few of many tests administered, and the test that would have been proposed in advance as the best measure of treatment effectiveness (the Wechsler Memory Scale's Logical Memory Test - Memory for stories) didn't pan out. The latest good prospective analysis of risk factors for Alzheimer's disease (Lindsay J, Laurin D, Verreault R, Hebert R, Helliwell B, Hill GB, McDowell I. Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol;156(5):445-53, 2002) found that use of nonsteroidal anti-inflammatory drugs, wine consumption, coffee consumption, and regular physical activity were associated with a reduced risk of Alzheimer's disease. No statistically significant association was found for family history of dementia, sex, history of depression, estrogen replacement therapy, head trauma, antiperspirant or antacid use, smoking, high blood pressure, heart disease, or stroke.

Kawas, C., Resnick, S., Morrison, A., Brookmeyer, R., Corrada, M., Zonderman, A., Bacal, C., Donnell Lingle, D., & Metter, E. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease. Neurology, 48, 1517-1521, 1997.

This study followed 472 women for 16 years as part of the Baltimore Longitudinal Study of Aging. Estrogen use was documented prospectively at each visit. The investigators used the Cox proportional hazards model and adjusted for education to estimate the risk of developing Alzheimer's disease (AD) in estrogen users compared with nonusers. The relative risk for developing AD was 0.46 in estrogen users, indicating a reduced risk of developing the disorder.

Our Comment: There does not yet appear to be a way to make estrogen therapy a powerful AD treatment agent. However, the mechanisms for the therapy's effectiveness make some sense and the studies still get funded. Not too many people are worried about the risk of getting cancer, if mild cognitive impairment is evident. The latest good prospective analysis of risk factors for Alzheimer's disease (Lindsay J, Laurin D, Verreault R, Hebert R, Helliwell B, Hill GB, McDowell I. Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol;156(5):445-53, 2002) found that use of nonsteroidal anti-inflammatory drugs, wine consumption, coffee consumption, and regular physical activity were associated with a reduced risk of Alzheimer's disease. No statistically significant association was found for family history of dementia, sex, history of depression, estrogen replacement therapy, head trauma, antiperspirant or antacid use, smoking, high blood pressure, heart disease, or stroke. Maybe women who take estrogens exercise more than those who don't.