Alzheimer's disease, estrogens, and clinical trials: A case study in drug development for complex disorders

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, affecting more than 4 million Americans, and it is a huge drain oil health care resources. Moreover, the cost burden of AD will increase substantially without the development of drugs that prevent its onset or slow its progression. At the present time, the available AD drugs provide, at best, temporary cognitive improvement, and cost-benefit analyses indicate no more than marginal support for their use. AD is a disorder of complex etiology that is characterized by the formation of amyloid plaques and neurofibrillary tangles in the brain. The Amyloid Cascade model of AD neurodegeneration postulates that the primary disease process is the deposition of amyloid plaques and their subsequent effects on cognition. However, as we review here, the emerging evidence argues against simple linear models of neurodegeneration in AD patients, and more complex models of etiology and pathogenesis are needed as part of the drug development process. As one potential therapeutic approach, there is substantial evidence that estrogens are neuroprotective and act on a number of neural pathways, many of which are compromised in AD. A number of studies have shown that estrogens provide clinical benefit in AD patients and in other neurodegenerative disorders. Unfortunately, the negative results of the Women's Health Initiative Memory Study (WHIMS) have overshadowed the positive results from the last four decades. However, as discussed here, there are a number of reasons why the WHIMS results should not be generalized. On balance, estrogens remain a fruitful drug development approach for AD, and other neurodegenerative conditions, and especially those estrogen compounds or analogues that avoid or minimize the complications associated with long-term use of feminizing hormones in post-menopausal women.