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 epsilon 4 allele related to earlier and faster cognitive decline, but possession of an APOE epsilon 2 related to slower decline. Patients homozygous for APOE epsilon 4 showed faster cognitive decline than heterozygotes. The linear model was less sensitive and did not detect differences between APOE epsilon 4 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 epsilon 4 allele, but the APOE epsilon 2 allele is protective. The nonlinear model yielded larger estimates of the maximal rate of decline than the linear.