title: The value and limitations of transgenic mouse models used in drug discovery for Alzheimer's disease: an update.
abstract: BACKGROUND
  The exponential growth in the world's aged population has increased pressure on drug discovery efforts to identify innovative therapies for Alzheimer's disease (AD). The long and uncertain clinical trial path utilized to test the potential efficacy of these novel agents is challenging. For these and other reasons, there has been an explosion in the generation and availability of transgenic mouse models that mimic some, but not all aspects of AD. The largely overwhelmingly positive results obtained when testing potential clinical agents in these same animal models have failed to translate into similar positive clinical outcomes.
  
  
  METHODS
  This review discusses the value and limitations associated with currently available transgenic mouse models of AD. Furthermore, the article proposes ways in which researchers can better characterize pharmacodynamic and pharmacokinetic endpoints to increase the success rate for novel therapies advancing into clinical development. Lastly, the author discusses ways in which researchers can supplement, expand and improve transgenic mouse models used in AD drug discovery.
  
  
  CONCLUSIONS
  The use of transgenic mouse models that recapitulate various aspects of AD has expanded our knowledge and understanding of disease pathogenesis immensely. Further success in testing and translating novel therapies from animal models into bona fide medicines would be enhanced by i) the availability of better models that more fully recapitulate the disease spectrum, ii) defining and measuring standardized endpoints that display a pharmacodynamic range, iii) building and including translatable biomarkers and iv) including novel endpoints that would be expected to translate into clinically beneficial outcomes.
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., Groton, CT 06340, USA. kelly.bales@pfizer.com
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Bales
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D055808:Drug Discovery; D006801:Humans; D007167:Immunotherapy / Q000379:methods* / Q000639:trends; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000276:immunology / Q000378:metabolism; D016875:tau Proteins / Q000276:immunology / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins