title: Biomarkers and cognitive endpoints to optimize trials in Alzheimer's disease.
abstract: OBJECTIVE
  To find the combination of candidate biomarkers and cognitive endpoints to maximize statistical power and minimize cost of clinical trials of healthy elders at risk for cognitive decline due to Alzheimer's disease.
  
  
  METHODS
  Four-hundred and twelve cognitively normal participants were followed over 7 years. Nonlinear methods were used to estimate the longitudinal trajectories of several cognitive outcomes including delayed memory recall, executive function, processing speed, and several cognitive composites by subgroups selected on the basis of biomarkers, including APOE-ε4 allele carriers, cerebrospinal fluid biomarkers (Aβ 42, total tau, and phosphorylated tau), and those with small hippocampi.
  
  
  RESULTS
  Derived cognitive composites combining Alzheimer's Disease Assessment Scale (ADAS)-cog scores with additional delayed memory recall and executive function components captured decline more robustly across biomarker groups than any measure of a single cognitive domain or ADAS-cog alone. Substantial increases in power resulted when including only participants positive for three or more biomarkers in simulations of clinical trials.
  
  
  CONCLUSIONS
  Clinical trial power may be improved by selecting participants on the basis of amyloid and neurodegeneration biomarkers and carefully tailoring primary cognitive endpoints to reflect the expected decline specific to these individuals.
authors.affiliation: Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases San Francisco, California ; Department of Radiology and Biomedical Imaging, University of California San Francisco, California.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Insel
authors.affiliation: Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases San Francisco, California ; Department of Radiology and Biomedical Imaging, University of California San Francisco, California ; Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg Mölndal, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Mattsson
authors.affiliation: Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases San Francisco, California ; Department of Psychiatry, University of California San Francisco, California.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Mackin
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, California.
authors.forename: John
authors.initials: J
authors.lastname: Kornak
authors.affiliation: Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases San Francisco, California.
authors.forename: Rachel
authors.initials: R
authors.lastname: Nosheny
authors.affiliation: Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases San Francisco, California ; Department of Radiology and Biomedical Imaging, University of California San Francisco, California.
authors.forename: Duygu
authors.initials: D
authors.lastname: Tosun-Turgut
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Family and Preventive Medicine, University of California San Diego, California ; Department of Neurosciences, University of California San Diego, California.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Donohue
authors.affiliation: Department of Neurosciences, University of California San Diego, California.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Aisen
authors.affiliation: Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases San Francisco, California ; Department of Radiology and Biomedical Imaging, University of California San Francisco, California.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner