The effect of APOE-epsilon4 on dementia is mediated by Alzheimer neuropathology.

The degree to which the association of epsilon4 with dementia is mediated by AD lesions in comparison with vascular lesions is controversial. The present study was undertaken to determine the roles of Alzheimer disease (AD) and vascular pathology in mediating the effect of apolipoprotein E (APOE)-epsilon4 alleles on dementia. Clinicopathologic correlations were studied in 267 Catholic sisters participating in the Nun Study. The extent to which AD and vascular pathologies mediated the effect of APOEepsilon4 on dementia was investigated using multiple logistic regression. Adjusted for age at death and education, possession of 1 or more epsilon4 alleles was an important risk factor for dementia (odds ratio=2.98; 95% confidence interval, 1.62-5.48). This association was lost (odds ratio=1.38; 95% confidence interval, 0.68-2.80) when an index of the severity of AD-related neuropathology was added to the model, but changed little when measures of the severity of vascular pathology were added. The findings suggest that the effect of epsilon4 on dementia is mediated by the severity of AD pathology. Although infarcts and atherosclerosis contribute to the occurrence of dementia, this contribution seems unrelated to APOE genotype.