title: Requiring an amyloid-beta1-42 biomarker for prodromal Alzheimer's disease or mild cognitive impairment does not lead to more efficient clinical trials.
abstract: BACKGROUND
  Low cerebrospinal fluid (CSF) amyloid-beta(1-42) concentration and high total-tau/Abeta(1-42) ratio have been recommended to support the diagnosis of prodromal Alzheimer's disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and also to select patients for clinical trials (Shaw et al, Ann Neurol 2009;65:403-13; Dubois et al, Lancet Neurol 2007;6:734-46).
  
  
  METHODS
  We tested this recommendation with clinical trials simulations using patients from the Alzheimer Disease Neuroimaging Initiative who fulfilled the following entry criteria: (1) aMCI, (2) aMCI with CSF Abeta(1-42) <or=192 mg/mL, (3) and aMCI with total-tau/Abeta(1-42) >0.39. For each criterion, we randomly resampled the database obtaining samples for 1000 trials for each trial scenario, planning for 1 or 2 year trials with samples from 50 to 400 patients per treatment or placebo group, with up to 40% dropouts, outcomes after using the AD assessment scale-cognitive subscale and clinical dementia rating scale with effect sizes ranging from 0.15 to 0.75, and calculated statistical power.
  
  
  RESULTS
  Approximately 70% to 74% of aMCI patients with CSF measures met biomarker criteria. The addition of the low Abeta(1-42) or high tau/Abeta(1-42) requirement resulted in minimal or no increase in the power of the trials compared with enrolling aMCI without requiring the biomarker criteria. Slightly larger mean differences between the placebo and treatment groups fulfilling biomarker criteria were offset by increased outcome variability within the groups.
  
  
  CONCLUSIONS
  Although patients with aMCI or patients with prodromal AD meeting CSF biomarkers criteria were slightly more cognitively impaired and showed greater decline than patients with aMCI diagnosed without considering the biomarkers, the requirement of biomarker-positive patients would most likely not result in more efficient clinical trials, and trials would take longer because fewer patients would be available. A CSF Abeta(1-42) marker, however, could be useful as an explanatory variable or covariate when warranted by the action of a drug.
authors.affiliation: Department of Psychiatry, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. lschneid@usc.edu
authors.forename: Lon S
authors.initials: LS
authors.lastname: Schneider
authors.forename: Richard E
authors.initials: RE
authors.lastname: Kennedy
authors.forename: Gary R
authors.initials: GR
authors.lastname: Cutter
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000150:complications / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D014150:Antipsychotic Agents / Q000627:therapeutic use; D015415:Biomarkers; D002986:Clinical Trials as Topic; D003072:Cognition Disorders / Q000134:cerebrospinal fluid* / Q000150:complications / Q000188:drug therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D011569:Psychiatric Status Rating Scales; D016032:Randomized Controlled Trials as Topic; D013997:Time Factors; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D014150:Antipsychotic Agents; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
references.citation: Lancet Neurol. 2009 Jul;8(7):619-27
references.pmid: 19523877
references.citation: J Gerontol. 1982 May;37(3):323-9
references.pmid: 7069156
references.citation: Ann Neurol. 2006 Mar;59(3):512-9
references.pmid: 16372280
references.citation: Alzheimers Dement. 2005 Jul;1(1):55-66
references.pmid: 17476317
references.citation: Arch Neurol. 2011 Jan;68(1):58-66
references.pmid: 21220675
references.citation: JAMA. 2009 Jul 22;302(4):385-93
references.pmid: 19622817
references.citation: Psychol Med. 2010 Jan;40(1):135-45
references.pmid: 19863841
references.citation: Lancet Neurol. 2010 Jan;9(1):119-28
references.pmid: 20083042
references.citation: Neurology. 1993 Nov;43(11):2412-4
references.pmid: 8232972
references.citation: Arch Neurol. 2007 Mar;64(3):343-9
references.pmid: 17210801
references.citation: N Engl J Med. 2005 Jun 9;352(23):2379-88
references.pmid: 15829527
references.citation: Lancet Neurol. 2006 Mar;5(3):228-34
references.pmid: 16488378
references.citation: J Psychiatr Res. 1975 Nov;12(3):189-98
references.pmid: 1202204
references.citation: Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S13-21
references.pmid: 9236948
references.citation: Nat Rev Neurol. 2010 Mar;6(3):131-44
references.pmid: 20157306
references.citation: Lancet Neurol. 2007 Aug;6(8):734-46
references.pmid: 17616482
references.citation: Ann Neurol. 2009 Apr;65(4):403-13
references.pmid: 19296504
references.citation: Neurology. 2010 Jan 19;74(3):201-9
references.pmid: 20042704
references.citation: Stat Med. 2006 Dec 30;25(24):4279-92
references.pmid: 16947139
references.citation: J Biopharm Stat. 2009;19(2):227-46
references.pmid: 19212876
references.citation: Neurology. 2009 May 5;72(18):1555-61
references.pmid: 19176895
references.citation: Stat Med. 2005 Feb 15;24(3):329-39
references.pmid: 15551403
references.citation: Arch Neurol. 2010 Aug;67(8):949-56
references.pmid: 20697045
references.citation: Alzheimers Dement. 2009 Sep;5(5):388-97
references.pmid: 19751918