title: Combined Plasma and Cerebrospinal Fluid Signature for the Prediction of Midterm Progression From Mild Cognitive Impairment to Alzheimer Disease.
abstract: A reliable method of detecting Alzheimer disease (AD) in its prodromal state is needed for patient stratification in clinical trials or for personalizing existing or potential upcoming therapies. Current cerebrospinal fluid (CSF)- or imaging-based single biomarkers for AD offer reliable identification of patients with underlying AD but insufficient prediction of the rate of AD progression.
  
  
  
  To optimize prediction of progression from mild cognitive impairment (MCI) to AD dementia by combining information from diverse patient variables.
  
  
  
  This cohort study from the Alzheimer Disease Neuroimaging Initiative (ADNI) enrolled 928 patients with MCI at baseline and 249 selected variables available in the ADNI data set. Variables included clinical and demographic data, cognitive scores, magnetic resonance imaging-based brain volumetric data, the apolipoprotein E (APOE) and translocase of outer mitochondrial membrane 40 homolog (TOMM40) genotypes, and analyte levels measured in the CSF and plasma. Data were collected in July 2012 and analyzed from July 1, 2012, to June 1, 2015.
  
  
  
  Progression from MCI to AD within 1 to 6 years. To determine whether combinations of markers could predict progression from MCI to AD within 1 to 6 years, the elastic net algorithm was used in an iterative resampling of a training- and test-based variable selection and modeling approach.
  
  
  
  Among the 928 patients with MCI in the ADNI database, 94 had 224 of the required variables available for the modeling. The results showed the contributions of age, Clinical Dementia Rating Sum of Boxes composite test score, hippocampal volume, and multiple plasma and CSF factors in modeling progression to AD. A combination of apolipoprotein A-II and cortisol levels in plasma and fibroblast growth factor 4, heart-type fatty acid binding protein, calcitonin, and tumor necrosis factor-related apoptosis-inducing ligand receptor 3 (TRAIL-R3) in CSF allowed for reliable prediction of disease status 3 years from the time of sample collection (80% classification accuracy, 88% sensitivity, and 70% specificity).
  
  
  
  These study findings suggest that a combination of markers measured in plasma and CSF, distinct from β-amyloid and tau, could prove useful in predicting midterm progression from MCI to AD dementia. Such a large-scale, multivariable-based analytical approach could be applied to other similar large data sets involving AD and beyond.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California.
authors.forename: Benoit
authors.initials: B
authors.lastname: Lehallier
authors.affiliation: Translational Technologies and Bioinformatics, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd, Basel, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Essioux
authors.affiliation: Translational Technologies and Bioinformatics, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd, Basel, Switzerland.
authors.forename: Javier
authors.initials: J
authors.lastname: Gayan
authors.affiliation: Translational Technologies and Bioinformatics, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd, Basel, Switzerland.
authors.forename: Roxana
authors.initials: R
authors.lastname: Alexandridis
authors.affiliation: Roche Pharma Development, F. Hoffmann-La Roche, Ltd, Basel, Switzerland.
authors.forename: Tania
authors.initials: T
authors.lastname: Nikolcheva
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California4Center for Tissue Regeneration, Repair and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, California.
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
authors.affiliation: Neuroscience, Ophthalmology, and Rare Diseases Discovery and Translational Areas, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd, Basel, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Britschgi