THE ROLE OF APOE POLYMORPHISMS IN LATE-ONSET DEMENTIAS

Epidemiologic and laboratory results consistently implicate the APOE g ene in the pathogenesis of late-onset Alzheimer's disease (AD): the ep silon 4 allele increases risk in a dose-dependent fashion, while epsil on 2 confers protection. Individuals are susceptible for AD in varying degrees depending on which combination of APOE alleles has been inher ited, APOE promoter polymorphism and other factors. Deposition of both senile plaques and neurofibrillary tangles, the pathologic hallmarks of AD, are enhanced by epsilon 4 from the earliest lesions onward - di ffuse plaques consisting of A beta 1-42 and neurofibrillary tangles in the entorhinal cortex. Transgenic APOE mice carrying an APP mutation and 0, 1 or 2 copies of APOE showed dose-related increases in plaque d eposition in the hippocampus and cortex, a clear indication that APOEp promotes A beta deposition. The presence of each additional APOE epsi lon 4 allele leads to an earlier onset of the histopathological proces s of about 1 decade, on average. The association of both types of AD-r elated changes with the occurrence of epsilon 4 suggests that the APOE polymorphism causally contributes to the pathogenesis Of AD.