title: Evidence for ordering of Alzheimer disease biomarkers.
abstract: OBJECTIVE
  To empirically assess the concept that Alzheimer disease (AD) biomarkers significantly depart from normality in a temporally ordered manner.
  
  
  METHODS
  Validation sample.
  
  
  METHODS
  Multisite, referral centers.
  
  
  METHODS
  A total of 401 elderly participants in the Alzheimer's Disease Neuroimaging Initiative who were cognitively normal, who had mild cognitive impairment, or who had AD dementia. We compared the proportions of 3 AD biomarker values (the Aβ42 level in cerebrospinal fluid [CSF], the total tau level in CSF, and the hippocampal volume adjusted for intracranial volume [hereafter referred to as the adjusted hippocampal volume]) that were abnormal as cognitive impairment worsened. Cut points demarcating normal vs abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples.
  
  
  METHODS
  Three AD biomarkers (ie, the CSF Aβ42 level, the CSF total tau level, and the adjusted hippocampal volume).
  
  
  RESULTS
  Within each clinical group of the entire sample (n = 401), the CSF Aβ42 level was abnormal more often than was the CSF total tau level or the adjusted hippocampal volume. Among the 298 participants with both baseline and 12-month data, the proportion of participants with an abnormal Aβ42 level did not change from baseline to 12 months in any group. The proportion of participants with an abnormal total tau level increased from baseline to 12 months in cognitively normal participants (P = .05) but not in participants with mild cognitive impairment or AD dementia. For 209 participants with an abnormal CSF Aβ42 level at baseline, the percentage with an abnormal adjusted hippocampal volume but normal CSF total tau level increased from baseline to 12 months in participants with mild cognitive impairment. No change in the percentage of MCI participants with an abnormal total tau level was seen between baseline and 12 months.
  
  
  CONCLUSIONS
  A reduction in the CSF Aβ42 level denotes a pathophysiological process that significantly departs from normality (ie, becomes dynamic) early, whereas the CSF total tau level and the adjusted hippocampal volume are biomarkers of downstream pathophysiological processes. The CSF total tau level becomes dynamic before the adjusted hippocampal volume, but the hippocampal volume is more dynamic in the clinically symptomatic mild cognitive impairment and AD dementia phases of the disease than is the CSF total tau level.
authors.affiliation: Department of Radiology, Mayo Clinic and Mayo Foundation for Medical Education and Research, 200 First St, SW, Rochester, MN 55905, USA. jack.clifford@mayo.edu
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.forename: Prashanthi
authors.initials: P
authors.lastname: Vemuri
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Wiste
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Weigand
authors.forename: Paul S
authors.initials: PS
authors.lastname: Aisen
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Bernstein
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000503:physiopathology; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D016875:tau Proteins