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 ε4 alleles. If this relationship is due to increased rate of pathophysiological change, the presence of ε4 would be expected to influence progression of disease, predicting a more rapid decline with increasing number of ε4 alleles. Objective: To determine if the frequency of the ε4 allele of the apolipoprotein E (ApoE) gene affects the rate of clinical progression in AD. Setting: Alzheimer's Disease Research Center. Subjects: 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. Measurements: The subjects' characteristics and a 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. Design: 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 ε4 on clinical and cognitive measures. Results: The age at onset was greatest for the ε4-heterozygous subjects and least for the ε4-negative subjects. The heterozygous subjects declined more rapidly on the Mini-Mental State Examination and the Category Fluency Test than the subjects without the ε4 allele or with ε4 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 ε4 might predispose to the development of the disease without accelerating its pathogenesis or progression. The effects of ε4 on both age at onset and rate of decline need to be further investigated.