Apolipoprotein E genotype and rate of decline in probable Alzheimer's disease.
BACKGROUND
The risk of Alzheimer's disease (AD) appears to increase, and the age at onset to decrease, with the number of epsilon 4 alleles. If this relationship is due to increased rate of pathophysiological change, the presence of epsilon 4 would be expected to influence progression of disease, predicting a more rapid decline with increasing number of epsilon 4 alleles.


OBJECTIVE
To determine if the frequency of the epsilon 4 allele of the apolipoprotein E (ApoE) gene affects the rate of clinical progression in AD.


METHODS
Alzheimer's Disease Research Center.


METHODS
One hundred one subjects meeting criteria of the National Institute of Neurological Disorders and Stroke for probable AD or of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) for definite AD; 78 of these subjects met the additional criterion of having a Mini-Mental State Examination score of at least 10 for analysis of rate of decline.


METHODS
The subjects' characteristics and neuropsychological battery, including the Mini-Mental state Examination, Spatial Delayed Recognition Span, Boston Naming Test, Category Fluency Test, and the Physical Capacity Subscale of the Psychogeriatric Dependency Rating Scale.


METHODS
The subjects were followed up longitudinally for approximately one decade. Medical histories were taken and physical and neurologic examinations and neuropsychological testing were performed every 6 months. Three and a half years of data were available for most tests and 5.5 for the Psychogeriatric Dependency Rating Scale; thereafter, patients were no longer testable. A general linear model analysis of variance was used to assess the influence of ApoE on demographic characteristics and baseline performances on neuropsychological measures. A random-effects regression model was used to predict change over time associated with presence of epsilon 4 on clinical and cognitive measures.


RESULTS
The age at onset was greatest for the epsilon 4-heterozygous subjects and least for the epsilon 4-negative subjects. The heterozygous subjects declined more rapidly on the Mini-Mental State Examination and the Category Fluency Test than the subjects without the epsilon 4 allele or with epsilon homozygosity. The homozygous subjects declined faster on only one subscale: the Physical Capacity subscale of the Psychogeriatric Dependency Rating Scale. Covarying for age at onset did not affect the results.


CONCLUSIONS
The ApoE genotype does not strongly influence the rate of decline in AD, implying that epsilon 4 might predispose to the development of the disease without accelerating its pathogenesis or progression. The effects of epsilon 4 on both age at onset and rate of decline need to be further investigated.
Dal Forno
G
G
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Rasmusson
D X
DX
Brandt
J
J
Carson
K A
KA
Brookmeyer
R
R
Troncoso
J
J
Kawas
C H
CH
D017668:Age of Onset; D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics*; D018450:Disease Progression; D005787:Gene Frequency; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales
D053327:Apolipoprotein E4; D001057:Apolipoproteins E