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Arch Neurol. 2004 Nov;61(11):1743-8.

The natural history of Alzheimer disease: a longitudinal presymptomatic and symptomatic study of a familial cohort.

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Dementia Research Group, Institute of Neurology, London, England.



Knowledge of the evolution of cognitive deficits in Alzheimer disease is important for our understanding of disease progression. Previous reports, however, have either lacked detail or have not covered the presymptomatic stages.


To delineate the onset and progression of clinical and neuropsychological abnormalities in familial Alzheimer disease.


Nineteen subjects with familial Alzheimer disease underwent serial clinical and neuropsychological assessments. Eight of these had undergone presymptomatic assessments. The follow-up period was 1 to 10 years (mean, 5 years). The relative timing of the occurrence of 3 markers of disease onset and progression (onset of symptoms, Mini-Mental State Examination score < or = 24, and impaired scores on a range of neuropsychological tests) were compared using the binomial exact test.


Neurological abnormalities were not prominent, although myoclonus appeared early in some. Mini-Mental State Examination score was not sensitive to early disease. Memory and general intelligence deficits appeared at an earlier stage, in some patients when presymptomatic. Perceptual, naming, and especially spelling skills were preserved to a late stage.


Familial Alzheimer disease may have a long prodromal phase of several years with subtle deficits initially of general intelligence and memory, while spelling, naming, and perception are relatively preserved until a late stage.

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