Prodromal Alzheimer's disease: successive emergence of the clinical symptoms.
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.
Amieva
Hélène
H
Institut National de la Sante et de la Recherche Médicale, U897, France. helene.amieva@isped.u-bordeaux2.fr
Le Goff
Mélanie
M
Millet
Xavier
X
Orgogozo
Jean Marc
JM
Pérès
Karine
K
Barberger-Gateau
Pascale
P
Jacqmin-Gadda
Hélène
H
Dartigues
Jean François
JF
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