title: The clinical picture of Alzheimer's disease in the decade before diagnosis: clinical and biomarker trajectories.
abstract: OBJECTIVE
  Increasing evidence suggests that Alzheimer's disease begins at least a decade before the diagnosis of dementia. Earlier identification of the disease will have important implications for intervention; however, current models of preclinical changes are theoretical and require verification from empirical observations. Furthermore, these models have not incorporated psychiatric features.
  
  
  METHODS
  Clinical and biological markers were examined at baseline (1999-2001) in 9,076 people aged 65 years and older. A nested case-control study included 830 cases with Alzheimer's disease diagnosed by DSM-IV criteria during the 10-year follow-up and twice as many controls. By taking the distance between baseline and diagnosis as the length of the preclinical period, disease marker trajectories were estimated using nonparametric locally weighted smoothing analysis.
  
  
  RESULTS
  Significant differences for the cases compared to the controls were observed on both intercept and slope for truncated amyloid β40 (P = .006; P = .003, respectively), C-reactive protein (P = .03; P = .05), verbal fluency (P < .0001; P < .0001), visual recall (P < .0001; P = .007), and hippocampal volume (P = .0002; P = .04) and on the slope only for truncated amyloid β42 (P = .01). The cases showed higher levels of depressive symptoms (P = .003), which remained stable over the 10 years to diagnosis.
  
  
  CONCLUSIONS
  As hypothesized by existing theoretical models, changes in plasma amyloid β levels, hippocampal atrophy, cognitive loss, and C-reactive protein are already observed up to 10 years before diagnosis. An acceleration in cognitive decline appears to follow a significant increase in amyloid accumulation, and depressive symptomatology remains at a constantly higher level. Overall, clinical and biological markers do not follow the same trajectories; the clinical picture changes according to distance from dementia.
authors.affiliation: Inserm U1061, Hopital La Colombiere, 39 Ave C. Flahault, 34093 Montpellier Cedex 5, France karen.ritchie@inserm.fr.
authors.forename: Karen
authors.initials: K
authors.lastname: Ritchie
authors.forename: Isabelle
authors.initials: I
authors.lastname: Carrière
authors.forename: Claudine
authors.initials: C
authors.lastname: Berr
authors.forename: Hélène
authors.initials: H
authors.lastname: Amieva
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dartigues
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Ancelin
authors.forename: Craig W
authors.initials: CW
authors.lastname: Ritchie
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000097:blood* / Q000150:complications / Q000175:diagnosis* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism*; D003072:Cognition Disorders / Q000150:complications / Q000175:diagnosis*; D003863:Depression / Q000150:complications / Q000175:diagnosis*; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D059906:Neuroimaging; D010446:Peptide Fragments / Q000097:blood*; D062706:Prodromal Symptoms; D066127:White Matter / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D002097:C-Reactive Protein