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

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, affecting more than 4 million Americans, and it is a huge drain on 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 costbenefit 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. Drug Dev. Res. 66:53-77, 2006.

Novel Perspectives for Progesterone in Hormone Replacement Therapy, with Special Reference to the Nervous System

“…Their outcome has been extensively commented upon in the recent literature and has brought many fundamental issues of hormone therapies to light, but discussions were mainly limited to the effects of estrogens (1)(2)(3)(4)(5). In fact, progestagens are generally only considered with respect to their usefulness in preventing uterine hyperplasia and malignancy in response to estrogens.…”

A comparative evaluation of treatments with 17β-estradiol and its brain-selective prodrug in a double-transgenic mouse model of Alzheimer's disease

“…The Women’s Health Initiative clinical trials have revealed improved cognition (Howell et al, 2006; Maki and Henderson 2012), although they relied on conjugated equine estrogen instead of E2, the main human estrogen, used in most basic science investigations. However, adverse side effects of the currently available estrogen therapies such as an increased incidence of breast cancer and circulatory system impacts, have been well known (Rossouw et al, 2002).…”

Mitochondrial Drugs Come of Age

“…Dating back to the 1990s, MitoKor was one of the most significant early ventures to focus on mitochondrial approaches to treating and diagnosing disease-no doubt ahead of its time, at least in our biased view (e.g., see Howell et al [2005], , Moos et al [2008Moos et al [ , 2009, and Pei et al [2003aPei et al [ , 2003b). A wealth of knowledge regarding mitochondrial targets, structures, and disease has accumulated in the interim.…”