Original ArticlesThe Effect of APOE-ε4 on Dementia is Mediated by Alzheimer NeuropathologyMortimer, James A. PhD*; Snowdon, David A. PhD†; Markesbery, William R. MD‡Author Information *Department of Epidemiology and Biostatistics, College of Public Health, University of South Florida, Tampa, FL Departments of †Neurology ‡Neurology and Pathology, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY Funded by grants P50-AG025711 (J.A.M.), R01-AG09862 (D.A.S.) and 1P30-AG28383 (W.R.M.) from the National Institute on Aging. Reprints: James A. Mortimer, PhD, Department of Epidemiology and Biostatistics, University of South Florida, 13201 Bruce B. Downs Boulevard, MDC-56, Tampa, FL 33612-3805 (e-mail: email@example.com). Received for publication June 18, 2008; accepted September 13, 2008 Alzheimer Disease & Associated Disorders: April-June 2009 - Volume 23 - Issue 2 - p 152-157 doi: 10.1097/WAD.0b013e318190a855 Buy Metrics Abstract The degree to which the association of ε4 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)-ε4 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 APOE-ε4 on dementia was investigated using multiple logistic regression. Adjusted for age at death and education, possession of 1 or more ε4 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 ε4 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. © 2009 Lippincott Williams & Wilkins, Inc.