title: Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people.
abstract: OBJECTIVE
  To identify biomarker patterns typical for Alzheimer disease (AD) in an independent, unsupervised way, without using information on the clinical diagnosis.
  
  
  METHODS
  Mixture modeling approach.
  
  
  METHODS
  Alzheimer's Disease Neuroimaging Initiative database.
  
  
  METHODS
  Cognitively normal persons, patients with AD, and individuals with mild cognitive impairment.
  
  
  METHODS
  Cerebrospinal fluid-derived beta-amyloid protein 1-42, total tau protein, and phosphorylated tau(181P) protein concentrations were used as biomarkers on a clinically well-characterized data set. The outcome of the qualification analysis was validated on 2 additional data sets, 1 of which was autopsy confirmed.
  
  
  RESULTS
  Using the US Alzheimer's Disease Neuroimaging Initiative data set, a cerebrospinal fluid beta-amyloid protein 1-42/phosphorylated tau(181P) biomarker mixture model identified 1 feature linked to AD, while the other matched the "healthy" status. The AD signature was found in 90%, 72%, and 36% of patients in the AD, mild cognitive impairment, and cognitively normal groups, respectively. The cognitively normal group with the AD signature was enriched in apolipoprotein E epsilon4 allele carriers. Results were validated on 2 other data sets. In 1 study consisting of 68 autopsy-confirmed AD cases, 64 of 68 patients (94% sensitivity) were correctly classified with the AD feature. In another data set with patients (n = 57) with mild cognitive impairment followed up for 5 years, the model showed a sensitivity of 100% in patients progressing to AD.
  
  
  CONCLUSIONS
  The mixture modeling approach, totally independent of clinical AD diagnosis, correctly classified patients with AD. The unexpected presence of the AD signature in more than one-third of cognitively normal subjects suggests that AD pathology is active and detectable earlier than has heretofore been envisioned.
authors.affiliation: Innogenetics, Industriepark Zwijnaarde 7, Box 4, B-9052 Gent, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: De Meyer
authors.forename: Fred
authors.initials: F
authors.lastname: Shapiro
authors.forename: Hugo
authors.initials: H
authors.lastname: Vanderstichele
authors.forename: Eugeen
authors.initials: E
authors.lastname: Vanmechelen
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Peter Paul
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Els
authors.initials: E
authors.lastname: Coart
authors.forename: Oskar
authors.initials: O
authors.lastname: Hansson
authors.forename: Lennart
authors.initials: L
authors.lastname: Minthon
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.forename: Leslie
authors.initials: L
authors.lastname: Shaw
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D053327:Apolipoprotein E4 / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D003071:Cognition / Q000502:physiology*; D005260:Female; D005500:Follow-Up Studies; D015577:Geriatric Assessment; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D012372:ROC Curve; D015203:Reproducibility of Results; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins