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R O B E R T A D I A Z B R I N T O N , Ph.D., A N D L I Q I N Z H A O , Ph.D. Preclinical Efforts to Develop Effective NeuroSERMs for the Brain C H A P T E R F I V E Why Focus on Therapeutic Strategies to Prevent Alzheimer Disease? Neurodegenerative diseases are among the most devastating and costly ageassociated maladies. Of the neurodegenerative diseases, Alzheimer disease (AD) is the leading cause of dementia, loss of independent living, and institutionalization (Brookmeyer et al., 1998; Fillit, 2000, 2002a; Whitehouse, 1997). AD can have a prolonged gestational period until frank symptoms develop (up to 20 years), followed by an equally slow rate of debilitation over a period lasting from 1 to 15 years (Fillit et al., 2002). Age remains the greatest risk factor for developing AD, which typically presents in the mid-seventies and becomes most prevalent in the mid-eighties, with nearly 50 percent of octogenarians manifesting evidence of the disease. Conservative projections indicate that the prevalence of AD will nearly quadruple in the next 50 years, by which time one in 45 Americans will be afflicted with the disease (Brookmeyer et al., 1998). Currently, approximately 360,000 new cases of AD occur each year. To put these numbers into perspective , it is interesting to contrast the incidence of AD and that of AIDS. In the United States, 44,232 new cases of AIDS were reported to the U.S. Centers for Disease Control in 2003, compared with 360,000 new cases of AD (Centers for Disease Control, 2005). In the current therapeutic environment the number of new AD cases is projected to rise more than threefold, from 360,000 new cases per year in 1997 to 1.14 million new cases per year in 2047. In the United States alone, the cost of caring for the 4 million persons who currently have AD is approximately $100 billion per year (Fillit, 2000, 2002a). By 2050, if the rates do not change and if no effective preventive therapies are developed, 14 million older Americans are expected to have AD (Fillit, 2000, 2002a). Gender Demographics of AD: A Women’s Health Issue Despite high-profile cases such as those of Ronald Reagan, Charlton Heston , and Sargent Shriver, women are by far the principal victims of AD (Brinton , 1999; Fillit, 2002b). Of those affected by AD, 68 percent are female and 32 percent are male (Brookmeyer et al., 1998). Because women have a longer life expectancy than men, the number of women with AD exceeds the number of men. Moreover, a double danger exists for women: the results of a metaanalysis of seven sex-specific studies concluded that women are 1.5 times more likely to develop AD than age-matched men (Gao et al., 1998), a conclusion supported by the Cache County cohort analysis, which showed a clear female gender increase in the incidence of AD (Zandi, Carlson, et al., 2002). At the turn of the twenty-first century, there were nearly 42 million women over the age of 50 in the United States, and of these, more than 31 million were over the age of 55 (North American Menopause Society, 2003). In the United States, 50 million women are expected to be 55 or older by the year 2020. Currently, a woman’s average life expectancy is estimated to be 79.7 years. A woman who reaches the age of 54, however, can expect to live to 84, and nearly two-thirds of the total U.S. population will survive to age 85 or older. Based on these data, women can anticipate spending one-third to one-half of their lifetime in the postmenopausal state. Current epidemiological data indicate that of the 18 million American women now in their seventies and eighties, almost half will manifest the histopathological changes of AD (Henderson , 2000a). Worldwide, more than 470 million women are 50 years old or older, and 30 percent of those are projected to live into their eighties (North American Menopause Society, 2003). The potential impact of AD on society as a whole is overwhelming, because the disease affects both sexes. The projected exponential increase in the prevalence of AD, along with the anticipated impact on families and society, highlights the importance of developing strategies to prevent AD. N E U R O S E R M S F O R T H E B R A...

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