Complexities In The Existing Literature

The data discussed in this chapter suggest that dietary intake of soy protein including the isoflavones, has health benefits in the primate brain that may protect against AD-relevant protein modifications involving the microtubule protein tau. Thus, these data suggest that incorporating soy containing isoflavones into human diets may be neuroprotective. Yet scientific data are never perfect, and in this relatively new area of research on the effects of soy in the nervous system, the data are both sparse and complex. An epidemiological study that followed the dietary patterns of a group of elderly Japanese men in Hawaii found a link between high tofu consumption and increased incidence of dementia, and reduced brain size at death (White et al., 2000). While the raw data were undeniable, the conclusion that higher tofu consumption was correlated with increased incidence of dementia is difficult to reconcile with the documented health benefits of soy and the lower incidence of dementia in Asian countries. However, until the molecular mechanisms that underlie AD pathology, and the increased risk for dementia caused by estrogen loss, are better understood, the epidemiological data of White et al. (2000) remain poorly understood, yet unchallenged.

If estrogen loss predisposed elderly women to AD, it is possible that estrogen treatment may have therapeutic effects for AD patients. But a recently completed clinical trial demonstrated that in already-diagnosed AD patients, estrogen therapy was not effective in either attenuating symptoms, or in slowing progression of the neurodegeneration, demonstrating that estrogen therapy is not a viable option for AD patients (Mulnard et al., 2000). The preponderance of the experimental data, however, predicted that estrogen treatment of already-diagnosed AD patients would not have beneficial effects. It is extremely critical to consider whether qualitatively different effects would have been obtained if a clinical trial had been carried out with women at risk for, but not yet diagnosed with, AD. Given the public health issues involved, such a clinical trial, expensive and long term though it may be, may be the only way to determine whether giving estrogen or estrogen alternatives in the pre-menopausal period, or pre-AD, will have efficacy in delaying the onset or incidence of AD in elderly women.

Although it appears that estrogen has no therapeutic effectiveness once neurodegeneration has been diagnosed, the concept of premenopausal treatment, particularly with a benign estrogen-alternative such as soy, to protect against a decline in cognitive function, or progression to pathology, is valid. Pan et al. (1999) showed that dietary soy isoflavones mimicked estrogen action in inhibiting ovariectomy-induced reduction in the mRNAs of critical brain proteins. More compelling, however, was the evidence that dietary soy isoflavones, against a casein protein background, protected (again like estrogen) against ovariectomy-induced decline in cognitive function in rodents (Pan et al., 2000).

Thus, while the epidemiological evidence suggested that postmenopausal estrogen-replacement therapy could lowers one's risk for AD, the clinical data strongly suggested that intervention after onset of disease was not effective (Wang et al., 2000). Limited animal behavior studies demonstrated that both estrogen and a dietary soy isoflavone fraction without soy protein protected against ovariectomy-induced cognitive dysfunction, suggesting that either estrogen or soy isoflavones, prior to the development of neurodegeneration, could be protective, as Shaywitz and Shaywitz have proposed (2000). Finally, our biochemical studies of the effects of soy vs. Premarin™ in the brain, in a primate model of menopause, indicated that soy can potentially protect against the development of pathology in the brain, but the mechanisms may be different, possibly complementary, to those of estrogen.

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