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From the Oxford Project to Investigate Memory and Ageing, Department of Pharmacology, Oxford University, UK.
Address correspondence and reprint requests to Dr. J. Williams, OPTIMA, Radcliffe Infirmary, Woodstock Road, Oxford, OX2 6HE, UK; e-mail: Jonathan.Williams{at}pharm.ox.ac.uk
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 
4 allele related to earlier and faster cognitive decline, but possession of an APOE 2 related to slower decline. Patients homozygous for APOE 4 showed faster cognitive decline than heterozygotes. The linear model was less sensitive and did not detect differences between APOE 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 4 allele, but the APOE 2 allele is protective. The nonlinear model yielded larger estimates of the maximal rate of decline than the linear.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the December 27 issue to find the title link for this article.
Editorial, see page 1855
Supported by Phytopharm plc., the Takayama Foundation and the Health Foundation.
Disclosure: The authors report no conflicts of interest.
Received October 12, 2004. Accepted in final form August 22, 2005.
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Neurology 2005 65: 1855-1856.
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