Journal of Alzheimer’s Disease 6 (2004) S27–S35 S27IOS PressRequirements of a brain selective estrogen:Advances and remaining challenges fordeveloping a NeuroSERMRoberta Diaz Brinton∗Department of Molecular Pharmacology and Toxicology and the Program in Neuroscience, University of SouthernCalifornia, Pharmaceutical Sciences Center, Los Angeles, CA 90089, USAAbstract. Our goal is to develop therapeutic agents that prevent age-associated neurodegenerative disease such as Alzheimer’s.To achieve this goal, we are building on extensive knowledge regarding mechanisms of estrogen action in brain and theepidemiological human data indicating that estrogen/hormone therapy reduces the risk of developing Alzheimer’s disease whenadministered at the time of the menopause and continued over several to many years. The mechanisms of estrogen actionin neurons provides a systematic mechanistic rationale for determining why estrogen therapy is efficacious for prevention ofAlzheimer’s disease and why it is not efficacious for long-term treatment of the disease. Our preclinical research plan is a hybridof both discovery and translational research to develop a brain selective estrogen receptor modulator (SERM). We have termedsuch molecules NeuroSERMs to denote their preferential selectivity for activating estrogen mechanisms in brain. Our strategyto develop NeuroSERMs is threefold: (1) determine the target of estrogen action in brain, specifically the estrogen receptor inhippocampal and cortical neurons required for the neurotrophic and neuroprotective actions of estrogen; (2) develop NeuroSERMcandidate molecules using three in silico discovery and design strategies and (3) determine the neurotrophic and neuroprotectiveefficacy of candidate molecules using neuronal responses predictive of clinical efficacy. Using an academic translational researchmodel, a team of scientists with expertise in molecular biology, computational chemistry, synthetic chemistry, proteomics,neurobiology and mitochondrial function have been assembled along with state of the art technologies required to developcandidate NeuroSERM molecules.Keywords: Therapeutics, estrogen, Alzheimer’s disease, neuroprotection, neurons1. Introduction1.1. Why focus on therapeutic strategies to preventAlzheimer’s diseaseOf the age-associated maladies, neurodegenerativediseases are among the most devastating and costly.Of these neurodegenerative diseases, Alzheimer’s isthe leading cause of dementia, loss of independent liv-∗Corresponding author: Roberta Diaz Brinton, Ph.D., MolecularPharmacology and Toxicology, University of Southern California,Pharmaceutical Sciences Center, 1985 Zonal Avenue, Los Angeles,CA 90089, USA. Tel.: +1 323 442 1430; Fax: +1 323 442 1489;E-mail: [email protected] and institutionalization [1–4]. Alzheimer’s diseasecan have a prolonged gestational period until franksymptomatology develops (up to 20 yrs), followed byan equally slow rate of debilitation ranging from 1–15 yrs [5].Age remains the greatest risk factor for develop-ing Alzheimer’s disease which typically presents in themid70’s and becomes most prevalent in the mid80’swith nearly 50% of octogenarians manifesting the dis-ease. Conservative projections predict that the preva-lence of Alzheimer’s disease will nearly quadruple inthe next 50 years, by which time 1 in 45 Americans willbe afflicted with the disease [1]. Currently, ∼ 360,000new cases of Alzheimer’s disease occur each year. Toput these numbers in some perspective, it is interest-ISSN 1387-2877/04/$17.00  2004 – IOS Press and the authors. All rights reservedS28 R.D. Brinton / NeuroSERMS for Prevention of ADing to contrast the incidence of AD with that of AIDS.In the US, 42,745 new cases of AIDS were detectedby the US Center for Disease Control in 2002 com-pared to the 360,000 new cases of Alzheimer’s disease(http://www.cdc.gov/nchs/fastats/aids-hiv.htm). Underthe current therapeutic environment, the number of newAD cases is projected to rise more than 3-fold, from360,000 cases per year in 1997 to 1.14 million newcases per year in 2047. The national cost of caring for4 million persons currently suffering from AD is ap-proximately $100 billion dollars per year in the UnitedStates alone [3,6]. By 2050, 14 million older Amer-icans are expected to have Alzheimer’s disease if thecurrent numbers hold and no preventive treatments be-come available [3,6].1.2. Gender demographics of Alzheimer’s disease: Awomen’s health issueDespite high profile cases such as Ronald Reagan,Charlton Heston and most recently Sargent Shriver,women are by far the principal victims of Alzheimer’sdisease [7,8]. Of those affected with Alzheimer’s dis-ease, 68% are female and 32% are male [1]. Becausewomen have a longer life expectancy than men, theabsolute number of women with Alzheimer’s diseaseexceeds that of men. However, a double danger ex-ists for women. Results of a meta-analysis of 7 sex-specific studies concluded that women are 1.5 timesmore likely to develop AD than men [9]. These datawere supported by the Cache County analysis whichshowed a clear female gender increase in the incidenceof AD [10].At the turn of the new millennium in the UnitedStates, there were nearly 42 million women over theage of 50 and of these, more than 31 million womenwere over the age of 55 [11]. By the year 2020 in theUS, 50 million women are estimated to be over the ageof 55. Currently, a woman’s average life expectancyis estimated at 79.7 years. However, a woman whoreaches the age of 54 can expect to live to the age of 84.3years. Nearly two-thirds of the total U.S. populationwill survive to age 85 or greater. Based on these data,women can anticipate spending one-third to one-halfof their lifetime in the menopausal state. Based on cur-rent epidemiological data, of the 18 million Americanwomen in their 70s–80s, 40–50% can be expected tomanifest the histopathological changes of Alzheimer’sdisease [12]. Worldwide, there are currently more than470 million women aged 50-plus, and 30% of those areprojected to live into their 80s [11].The potential impact of Alzheimer’s disease on so-ciety as a whole is overwhelming as the disease, al-though more prevalent in women, affects both sexes.The projected exponential increase in the prevalenceof AD, along with the anticipated impact on familiesand society, highlights the imperative for developingstrategies for prevention of Alzheimer’s disease.Our