Estrogen Replacement Therapy for Treatment of Mild to Moderate Alzheimer’s Disease
abstract & commentary
Synopsis: When given to symptomatic women, conjugated equine estrogens did not slow the progression of Alzheimer’s disease.
Source: Mulnard RA, et al. JAMA 2000;283: 1007-1015.
This double-blind, placebo-controlled, randomized, prospective multicenter trial was designed to determine if oral estrogen therapy would slow the progression of dementia in women with established Alzheimer’s disease. To better test this hypothesis, the study population was confined to women who had undergone a hysterectomy and could therefore take unopposed estrogen and to those who did not meet criteria for depression (n = 120). Eligible women were randomized to one of three arms: placebo, conjugated equine estrogen (CEE) 0.625 mg daily, and CEE 1.25 mg orally daily for one year. Several psychometric inventories were used to monitor response to interventions.
The results showed that estrogen did not retard the progression of dementia at any of the time points (2, 6, 12, and 15 months) except for a transient benefit seen in a low-dose CEE-treated group at two months. This benefit did not persist. Women on antidementia therapies (donepezil or tacrine) showed the same response as those not taking them. The rate of adverse events was statistically comparable in all groups, although two women in each CEE arm had a deep vein thrombosis (DVT), while none in the placebo arm did. Mulnard and colleagues conclude that estrogen is not effective for slowing the progression of established Alzheimer’s dementia.
COMMENT BY SARAH L. BERGA, MD
The most important message of this study is that estrogen therapy is not indicated as an intervention with established dementia. However, it is critical to emphasize that this does not mean that it is ineffective in preventing dementia or enhancing cognitive functioning in symptomatic, recently menopausal women. Estrogen therapy for menopausal women has only recently been touted as a potential cure for established disease. Previously, the mindset was that estrogen therapy was to be taken as a prophylactic against a variety of age-related diseases such as cardiovascular disease, osteoporosis, and urogenital atrophy. Why the switch in emphasis from prophylaxis to intervention? It is theoretically easier to determine if a given agent reverses or retards an established process. However, intervening once a pathologic process is well under way also raises the bar in terms of required potency. It seems too much to expect a prophylactic to undo neurofibrillary tangles and restore dead glia, melt away vessel occlusions in coronary arteries, tighten sagging pelvic ligaments, or rebuild broken cytoarchitectural struts in bone. As the addage says, "An ounce of prevention is worth a pound of cure." To my way of thinking, in the rush to show the power of estrogens, several investigative groups undertook clinical challenges of unrealistic proportions. These null studies in no way invalidate the prior mindset that estrogen therapy may help to retard disease development. However, to determine the magnitude of prophylactic benefits demands that a larger population be followed for a much longer duration. Such studies not only take a long time, but they are expensive and may not lead to much academic reward for the investigators. Sadly, the only long-term prospective, randomized, double-blind trial that is likely to yield interpretable data about multiple simultaneous end points is the Women’s Health Initiative. And that study will only be a test of CEE taken orally with and without medroxyprogesterone acetate. In the interim, the burden of proof is likely to be shifted. We previously supposed that the benefits of postmenopausal hormone therapy were likely to outweigh the risks of venous thrombolic events and breast cancer. I suspect that most women will now want more evidence that this is the case and we simply do not have concrete proof that this is so. Dialogues with patients regarding the pros and cons of postmenopausal hormone use are likely to take even longer.
About three weeks after the present report, another regarding Alzheimer’s dementia (AD) appeared in the Journal of the American Medical Association (Naslund J, et al. JAMA 2000;283:1571-1577). This report presented new data regarding the pathogenesis of AD. The report showed amyloid plaque accumulation (rather than tangles) upon autopsy correlated quantitatively with degree of dementia. In the accompanying editorial (Selkoe DJ. JAMA 2000;283:1615-1617), an analogy was made between diffuse plaques in AD and early fatty streaks in the genesis of atherosclerosis. Based on this report and other supporting evidence, the therapeutic target for preventing AD is now established to be amyloid b-peptide (Ab). Mulnard et al suggest that in the future, we will be screening for AD with blood tests for relevant gene defects, measurement of plasma Ab, and possibly cerebrospinal fluid levels of Ab and other key markers if neuropathology is suspected. Those at high risk or with early but clinically silent disease will then receive targeted aggressive therapies directed at the key pathophysiologic steps in much the same way that those with elevated low-density lipoprotein (LDL) are supposed to receive statins before their first myocardial infarction (MI). In all likelihood, estrogen will resume its role as a preventive rather than interventive for dementia and many other pathologic processes. The key questions will then be: which estrogen, by which route, for what duration, at what dose, and how to monitor?
20. Which of the following statements regarding Alzheimer’s dementia is true?
a. Disease severity of AD correlates with neurofibrillary tangles.
b. Postmenopausal estrogen therapy retards disease progression in women with moderate Alzheimer’s disease.
c. In general, it is harder to reverse an established disease process than to prevent it.
d. Estrogen therapy will prevent AD only if started early and continued indefinitely.
e. Vitamin E therapy has been shown to be more efficacious than estrogen therapy for the prevention of AD in women.
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