The role of APOE polymorphisms in late-onset dementias.
Epidemiologic and laboratory results consistently implicate the APOE gene in the pathogenesis of late-onset Alzheimer's disease (AD): the epsilon 4 allele increases risk in a dose-dependent fashion, while epsilon 2 confers protection. Individuals are susceptible for AD in varying degrees depending on which combination of APOE alleles has been inherited, 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--diffuse 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 deposition in the hippocampus and cortex, a clear indication that APOEp promotes A beta deposition. The presence of each additional APOE epsilon 4 allele leads to an earlier onset of the histopathological process of about 1 decade, on average. The association of both types of AD-related changes with the occurrence of epsilon 4 suggests that the APOE polymorphism causally contributes to the pathogenesis of AD.
Corder
E H
EH
Odense University, Denmark. E-Corder@WIN-CHS.ou.dk
Lannfelt
L
L
Bogdanovic
N
N
Fratiglioni
L
L
Mori
H
H
D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D001921:Brain / Q000473:pathology; D003704:Dementia / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D016874:Neurofibrillary Tangles / Q000473:pathology; D011110:Polymorphism, Genetic; D012307:Risk Factors; D016875:tau Proteins / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D016875:tau Proteins