. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24):2947-58. PubMed.

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  1. Hormone Replacement: Is There a Pony in Here Anywhere?
    In remembering President Reagan's optimistic outlook, several of his friends recounted the story that, when presented with a barn full of horse manure, Reagan would probably respond with the line, "There's gotta be a pony around here somewhere." Such steadfast optimism is the order of the day as investigators continue to pursue the tantalizing epidemiological evidence that hormone replacement therapy (HRT) might delay or prevent Alzheimer's. Two new papers add to the growing evidence that HRT is ineffective if begun too late, defined here as after age 65 years.

    Within the past five years, HRT has seen a dramatic reversal of fortune. Three independent studies established that HRT failed to slow cognitive decline. Just last year, two papers showed that combination estrogen/progestin (Prempro) could not delay or prevent Alzheimer's if begun at 65 years or later, and one of those even showed an increased risk for dementia among women on Prempro.

    One question that arose was whether estrogen alone might be the key, since most of the promising epidemiological data was derived from populations on conjugated equine estrogens (CEE). Only women who have had hysterectomies are eligible to receive CEEs, since this "unopposed" estrogen increases the risk of uterine cancer. Two new papers show that CEE treatment alone still conveys no obvious protection. Again, one of these showed increased risk of dementia with CEE use (Espeland et al., 2004; Shumaker et al., 2004; editorial by Lon Schneider).

    One strategy still remains and, ironically, it is the one that makes the most sense biologically for preventing Alzheimer's: perimenopausal HRT. The logic here is that "Surely prevention of a precipitous drop in estrogen levels makes more sense than suddenly restoring hormones after two decades of deficiency." One can imagine scenarios involving the molecular neuropathology: e.g., the amyloid precursor protein is rapidly induced during acute stress, and it is possible that menopause exerts such a stress. Only a Few epidemiological studies have addressed the possible preferential benefit of perimenopausal HRT, but a clear trend toward more benefit for those beginning HRT early has been documented (Zandi et al., 2002).

    While logical, there are many cautionary factors against embarking on such a study. HRT carries significant cardiovascular risks, and now the sole indication for HRT is for brief relief of hot flashes. Fosamax and raloxifene have supplanted HRT in the treatment or prevention of osteoporosis.

    Enter John Sperling, Silicon Valley tycoon, and founder of the Kronos Institute and the University of Phoenix Online. Kronos announced in April of this year the naming of eight centers nationwide that have begun recruiting over 700 women, ages 40 to 55 years, for a long-term Alzheimer's prevention trial.

    There might be a pony in here yet.—Sam Gandy.

    References:

    . Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24):2959-68. PubMed.

    . Estrogen and dementia: insights from the Women's Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24):3005-7. PubMed.

    . Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24):2947-58. PubMed.

    . Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA. 2002 Nov 6;288(17):2123-9. PubMed.