title: Prodromal Alzheimer's disease: successive emergence of the clinical symptoms.
abstract: OBJECTIVE
  Whereas cognitive deficits are known to be detectable long before the typical symptoms of Alzheimer's disease (AD) are evident, previous studies have failed to determine when cognitive functioning actually begins to decline before dementia. Utilizing the long follow-up of the PAQUID study, we examined the emergence of the first clinical symptoms over a 14-year period of follow-up before the dementia phase of AD.
  
  
  METHODS
  This study relies on a case-control sample selected from the PAQUID cohort. Of the 3,777 initial subjects of the cohort, 350 subjects experienced development of AD during the 14 years of follow-up. The cases were matched to 350 elderly control subjects. The evolution of scores on cognitive, functional, and depression scales was described throughout the 14-year follow-up using a semiparametric extension of the mixed-effects linear model.
  
  
  RESULTS
  The first decline in cognitive performances appeared as early as 12 years before dementia in measures of semantic memory and conceptual formation. Then, more global deficits appeared that were concomitant with an increase in memory complaints and depressive symptoms. About 2 years later, as a consequence of cognitive dysfunction, the subjects started to become slightly dependent in their activities of daily living. In the last 3 years, the impairment significantly worsened until the subjects reached the dementia phase.
  
  
  CONCLUSIONS
  This approach, describing the 14 years preceding dementia, provides a clear illustration of the particularly long and progressive prodromal phase of AD, and shows the successive emergence of cognitive deficits, depressive symptoms, and functional impairment during this phase.
authors.affiliation: Institut National de la Sante et de la Recherche Médicale, U897, France. helene.amieva@isped.u-bordeaux2.fr
authors.forename: Hélène
authors.initials: H
authors.lastname: Amieva
authors.forename: Mélanie
authors.initials: M
authors.lastname: Le Goff
authors.forename: Xavier
authors.initials: X
authors.lastname: Millet
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Orgogozo
authors.forename: Karine
authors.initials: K
authors.lastname: Pérès
authors.forename: Pascale
authors.initials: P
authors.lastname: Barberger-Gateau
authors.forename: Hélène
authors.initials: H
authors.lastname: Jacqmin-Gadda
authors.forename: Jean François
authors.initials: JF
authors.lastname: Dartigues
mesh_terms: D000203:Activities of Daily Living / Q000523:psychology; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology / Q000523:psychology; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000503:physiopathology / Q000523:psychology*; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000175:diagnosis* / Q000503:physiopathology / Q000523:psychology*; D015331:Cohort Studies; D015897:Comorbidity; D003866:Depressive Disorder / Q000175:diagnosis / Q000503:physiopathology / Q000523:psychology; D004185:Disability Evaluation; D018450:Disease Progression; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008569:Memory Disorders / Q000175:diagnosis / Q000503:physiopathology / Q000523:psychology; D009483:Neuropsychological Tests; D011237:Predictive Value of Tests; D013997:Time Factors