ASSOCIATION OF THE APOLIPOPROTEIN-E EPSILON-4 ALLELE WITH CLINICAL SUBTYPES OF AUTOPSY-CONFIRMED ALZHEIMERS-DISEASE

Consistent with previous reports, we observed a significant associatio n of the APOE epsilon 4 allele with Alzheimer's Disease (AD) in a seri es of 91 autopsy-confirmed cases. The epsilon 4 allele frequency was h igher in cases with a family history of AD-like dementia (0.54 +/- 0.0 7), although the epsilon 4 allele frequency in the AD cases with a neg ative family history (0.38 +/- 0.05) remained significantly greater th an that for the non-AD control group (0.13 +/- 0.03). A similar increa se in epsilon 4 allele frequency (0.54 +/- 0.07) was observed in the A D cases with amyloid angiopathy, compared to those who did not have am yloid angiopathy (0.36 +/- 0.04). Contrary to previous reports, no eff ect of the dosage of the epsilon 4 allele was found on the age of onse t of dementia among the AD cases and, contrary to reports suggesting a n association of epsilon 4 and atherosclerosis, the epsilon 4 allele f requency was similar in cases with or without concurrent brain infarct s. Modest but consistent correlations were observed between the dosage of epsilon 4 alleles and the cortical density of senile plaques, but not neurofibrillary tangles. The last finding suggests that the pathog enic events mediated by the epsilon 4 allele may be more directly invo lved in the formation of senile plaques, the identifying lesions in AD , than neurofibrillary tangles. A robust association of both the prese nce of an epsilon 4 allele and a family history of AD-like dementia wi th concurrent amyloid angiopathy occurred within our sample of AD case s. This association arose from an interaction of the epsilon 4 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 as sociated with the transmission of the APOE epsilon 4 allele. (C) 1994 Wiley-Liss, Inc.