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 ε4 allele related to earlier and faster cognitive decline, but possession of an APOE ε2 related to slower decline. Patients homozygous for APOE ε4 showed faster cognitive decline than heterozygotes. The linear model was less sensitive and did not detect differences between APOE ε4 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 ε4 allele, but the APOE ε2 allele is protective. The nonlinear model yielded larger estimates of the maximal rate of decline than the linear.