title: Predicting Reduction of Cerebrospinal Fluid β-Amyloid 42 in Cognitively Healthy Controls.
abstract: OBJECTIVE
  Alzheimer disease has a long preclinical stage characterized by β-amyloid (Aβ) accumulation without symptoms. Several trials focus on this stage and use biomarkers to include Aβ-positive participants, but an even earlier prevention of Aβ accumulation may be an effective treatment strategy.
  
  
  OBJECTIVE
  To determine whether people who appear to be Aβ negative but are at high risk for Aβ positivity within the near future can be identified.
  
  
  METHODS
  Longitudinal biomarker cohort study involving 35 cognitively healthy individuals who underwent cerebrospinal fluid (CSF) sampling for up to 3 years during the study (October 24, 2005, to September 1, 2014). All participants had normal CSF Aβ42 levels at baseline.
  
  
  METHODS
  Predictors of future Aβ positivity (levels of CSF Aβ42 declining below a previously validated cutoff level of 192 ng/L) tested by random forest models. Tested predictors included levels of protein in the CSF, hippocampal volume, genetics, demographics, and cognitive scores.
  
  
  RESULTS
  The CSF Aβ42 levels declined in 11 participants, and the CSF became Aβ positive. The baseline CSF Aβ42 level was a strong predictor of future positivity (accuracy, 79% [95% CI, 70%-87%]). Ten of 11 decliners had baseline CSF Aβ42 levels in the lower tertile of the reference range (<225 ng/L), and 22 of 24 nondecliners had baseline CSF Aβ42 levels in the upper 2 tertiles (≥225 ng/L). A high CSF P-tau level was associated with decline (accuracy, 68%; 95% CI, 55%-81%).
  
  
  CONCLUSIONS
  Baseline CSF Aβ42 levels in the lower part of the reference range are strongly associated with future Aβ positivity. This finding can be used in trials on very early prevention of Alzheimer disease to identify people at high risk for Aβ accumulation as defined by low CSF Aβ42 levels.
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden2Department of Radiology and Biomedical Imaging, University of California, San Francisco3Center for Imaging of Neur.
authors.forename: Niklas
authors.initials: N
authors.lastname: Mattsson
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco3Center for Imaging of Neurodegenerative Diseases, Department of Veterans Affairs Medical Center, San Francisco, California.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Insel
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Family and Preventive Medicine, University of California, San Diego, La Jolla.
authors.forename: Michael
authors.initials: M
authors.lastname: Donohue
authors.affiliation: Helen Wills Neuroscience Institute and School of Public Health, University of California, Berkeley.
authors.forename: William
authors.initials: W
authors.lastname: Jagust
authors.affiliation: Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Reisa
authors.initials: R
authors.lastname: Sperling
authors.affiliation: Alzheimer's Disease Cooperative Study, Department of Neurosciences, University of California, San Diego, La Jolla.
authors.forename: Paul
authors.initials: P
authors.lastname: Aisen
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco3Center for Imaging of Neurodegenerative Diseases, Department of Veterans Affairs Medical Center, San Francisco, California.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D062706:Prodromal Symptoms; D011379:Prognosis; D012016:Reference Values
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)