title: A paradigm shift for evaluating pharmacotherapy for Alzheimer's disease: the 10-patient screening protocol.
abstract: OBJECTIVE
  Discuss etiology of Alzheimer's disease (AD) and offer a paradigm shift-a change in basic assumptions-from present standards in clinical trials.
  
  
  METHODS
  PubMed search for studies into AD pathophysiology and assessment of disease progression. Searched terms: amyloid precursor protein/amyloid beta pathology, senile plaques, mitochondrial dysfunction, reactive oxygen species , advanced glycation end products, neuro-inflammation, dysfunctional microglia/astrocytes, proinflammatory cytokines, ApoE4 allele, Tau phosphorylation, Chlamydia pneumoniae, Dementia Severity Rating Scale, Clinical Dementia Rating Scale, Relative's Assessment of Global Symptomatology-Elderly, and Alzheimer's Disease Assessment Scale-cognitive.
  
  
  METHODS
  All prospective, randomized, placebo- or cohort-controlled, peer-reviewed English language publications from 1980 to 2012. Studies in animals, AD patients, and AD brain specimens.
  
  
  METHODS
  Objectives, methods, statistical design, and results reviewed to assess soundness of trials and validity of results. Trials with flawed methods or uninterpretable results excluded.
  
  
  RESULTS
  Primary pathophysiology comprises: amyloid precursor protein/amyloid beta pathology with deposition of senile plaques; mitochondrial dysfunction with insufficient ATP synthesis and release of reactive oxygen species; oxidative stress; and neuro-inflammation from dysfunction of microglia and astrocytes. Other factors include abnormal ApoE4 allele protein and aberrant Tau phosphorylation. Role of Chlamydia pneumoniae is unproven. Dementia Severity Rating Scale (DSRS) is optimal assessment tool for assessing AD progression.
  
  
  CONCLUSIONS
  AD's complex pathophysiology may require polypharmacy to mitigate symptoms and progression. DSRS-driven, 10-patient pilot studies offer practical, valid, and reliable screening for potentially effective pharmacotherapy in AD. The simplicity of this paradigm shift should expedite research and may promote earlier discovery of effective pharmacotherapy for AD.
authors.affiliation: Marshall University Joan C. Edwards Medical School, Huntington, West Virginia, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Weinstein
authors.forename: Edgar R
authors.initials: ER
authors.lastname: Gonzalez
authors.forename: Richard D
authors.initials: RD
authors.lastname: Egleton
authors.forename: David A
authors.initials: DA
authors.lastname: Hunt
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress
chemical_list: D016564:Amyloid beta-Protein Precursor