Association of the apolipoprotein E ϵ4 allele with clinical subtypes of autopsy‐confirmed Alzheimer's disease

Abstract

Consistent with previous reports, we observed a significant association of the APOE ϵ4 allele with Alzheimer's Disease (AD) in a series of 91 autopsy-confirmed cases. The ϵ4 allele frequency was higher in cases with a family history of AD-like dementia (0.54 ± 0.07), although the ϵ4 allele frequency in the AD cases with a negative family history (0.38 ± 0.05) remained significantly greater than that for the non-AD control group (0.13 ± 0.03). A similar increase in ϵ4 allele frequency (0.54 ± 0.07) was observed in the AD cases with amyloid angiopathy, compared to those who did not have amyloid angiopathy (0.36 ± 0.04). Contrary to previous reports, no effect of the dosage of the ϵ4 allele was found on the age of onset of dementia among the AD cases and, contrary to reports suggesting an association of ϵ4 and atherosclerosis, the ϵ4 allele frequency was similar in cases with or without concurrent brain infarcts. Modest but consistent correlations were observed between the dosage Of ϵ4 alleles and the cortical density of senile plaques, but not neurofibrillary tangles. The last finding suggests that the pathogenic events mediated by the ϵ4 allele may be more directly involved in the formation of senile plaques, the identifying lesions in AD, than neurofibrillary tangles. A robust association of both the presence of an ϵ4 allele and a family history of AD-like dementia with concurrent amyloid angiopathy occurred within our sample of AD cases. This association arose from an interaction of the ϵ4 allele with a separate familial factor for which a family history of dementia served as a surrogate. These results suggest that amyloid angiopathy may be a common or central feature of a form of familial AD that is associated with the transmission of the APOE ϵ4 allele.