Revolutionary advances in our understanding of the genetic and consequent cellular/biochemical etiologies of a group of phenotypically similar neurodegenerative disorders, referred to as Alzheimer’s Disease (AD), have heralded a new era in potential therapeutic intervention. To date, at least four genes have been identified which either cause early onset familial AD (APP/chr.21; presenilin1/chr.14; presenilin2/chr.1) or dramatically affect the relative risk for developing late onset AD (apoE/chr.19). The biological (viz. cellular) mechanism(s) by which mutations or polymorphisms in these genes contribute to disease pathogenesis are also becoming increasingly clear and have facilitated new approaches to therapeutic (especially pharmacological) intervention. I will review these findings, including recent data from our laboratory delineating an important role for apoE in amyloidogenesis in vivo, and present several ongoing approaches to drug discovery made possible by this new information. My presentation will illustrate several of the critical stages of drug discovery, including the identification of new biological targets, their validation by the creation of transgenic animal models, and the development of cellular (in vitro) and in vivo screens for lead identification/optimization. Similar approaches to other neuropsychiatric disorders will undoubtedly prove feasible once the genetic underpinnings of their etiologies are delineated.
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