APOE alleles predict the rate of cognitive decline in Alzheimer disease: a nonlinear model.
BACKGROUND
The APOE genotype predicts the age at onset of Alzheimer disease (AD) and neuropathologic progression. However, studies relating APOE alleles to the rate of cognitive decline have been inconclusive. This may stem from their use of linear statistical analyses.


OBJECTIVE
To model relations of APOE alleles to the rate of cognitive decline in AD, nonlinearly.


METHODS
Serial measures of cognitive ability were obtained using the cognitive scale of the Cambridge Examination for Mental Disorders of the Elderly in 218 patients with AD. The relations of these serial scores to APOE alleles were tested using nonlinear and linear mixed-effects models.


RESULTS
In the non-linear model, possession of an APOE epsilon4 allele related to earlier and faster cognitive decline, but possession of an APOE epsilon2 related to slower decline. Patients homozygous for APOE epsilon4 showed faster cognitive decline than heterozygotes. The linear model was less sensitive and did not detect differences between APOE epsilon4 homo- and heterozygotes.


CONCLUSIONS
APOE genotype strongly predicts the rate of cognitive decline in Alzheimer disease. The decline shows a dose-response relation with the APOE epsilon4 allele, but the APOE epsilon2 allele is protective. The nonlinear model yielded larger estimates of the maximal rate of decline than the linear.
Martins
C A R
CA
The Oxford Project to Investigate Memory and Ageing, Department of Pharmacology, Oxford University, UK.
Oulhaj
A
A
de Jager
C A
CA
Williams
J H
JH
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology*; D053329:Apolipoprotein E2; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics*; D003072:Cognition Disorders / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology*; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D005787:Gene Frequency; D005820:Genetic Testing; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D017711:Nonlinear Dynamics; D011110:Polymorphism, Genetic / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis
D053329:Apolipoprotein E2; D053327:Apolipoprotein E4; D001057:Apolipoproteins E