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4 allele, AD pathology, and the clinical expression of Alzheimer’s disease
From the Rush Alzheimer’s Disease Center and Rush Institute for Healthy Aging (Drs. Bennett, Wilson, Schneider, Evans, Aggarwal, and Bienias); Department of Neurological Sciences (Drs. Bennett, Wilson, Schneider, Evans, Aggarwal, Cochran, and Berry-Kravis); Department of Psychology (Dr. Wilson); Department of Pathology (Drs. Schneider and Cochran); Department of Internal Medicine (Drs. Evans and Bienias), Department of Pediatrics (Dr. Berry-Kravis), Rush Presbyterian-St. Luke’s Medical Center, Chicago, IL; and the Center for Neurobiology and Behavior (Dr. Arnold), University of Pennsylvania, Philadelphia.
Address correspondence and reprint requests to Dr. David A. Bennett, Rush Alzheimer’s Disease Center, 1645 W. Jackson, Suite 675, Chicago, IL 60612; e-mail: dbennett{at}rush.edu
Objective: To test the hypothesis that the APOE 
4 allele is associated with the clinical manifestations of AD through an association with the pathologic hallmarks of disease.
Methods: Participants were older Catholic nuns, priests, and brothers who agreed to annual neurologic and neuropsychological evaluation for AD and other common neurologic conditions and brain autopsy at the time of death. There were 77 persons without dementia and 51 with probable AD; 38 participants had one or more 4 alleles.
Results: In logistic regression analyses, controlling for age, sex, and education, the 4 allele was strongly associated with the likelihood of clinical AD (odds = 3.46, 95% CI = 1.44 to 8.33). However, controlling for the effect of AD pathology, the association of the allele with clinical AD was reduced by >50% and was no longer significant (odds = 1.58, 95% CI = 0.56 to 4.43). Similarly, in linear regression analyses, controlling for age, sex, and education, the 4 allele was strongly associated with level of cognitive function proximate to death (regression coefficient = -0.477, p = 0.005). However, after controlling for the effect of AD pathology, the association of the 4 allele with level of cognition was reduced by >80% and was no longer significant (regression coefficient = -0.093). Similar results were found in analyses using separate measures of neuritic plaques, diffuse plaques, and neurofibrillary tangles, and in analyses of five different cognitive systems (episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability).
Conclusions: The APOE 4 allele appears to be associated with the clinical manifestations of AD through an association with the pathologic hallmarks of AD rather than another mechanism.
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