Contribution of <i>APOE</i> promoter polymorphisms to Alzheimer’s disease risk

Abstract

<b><i><i>Objective:</i></i></b> To determine whether the effects of <i>APOE</i> promoter polymorphisms on AD are independent of the <i>APOE</i>-ε4 allele. <b><i><i>Background:</i></i></b> Recently, the −491 A→T and −219 G→T polymorphisms located in the <i>APOE</i> promoter have been suggested to be risk factors for AD. However, the effects of these polymorphisms have not always been reproduced in case-control studies, possibly because of the strong linkage disequilibrium existing at this locus or the characteristics of the populations studied. <b><i><i>Methods:</i></i></b> Data collection was performed from six independent samples (1,732 patients with AD and 1,926 control subjects) genotyped for <i>APOE</i> exon 4 and the two <i>APOE</i> promoter polymorphisms. The risks associated with the <i>APOE</i> polymorphisms for developing AD were estimated using logistic regression procedures and calculation of odds ratios with 95% CI adjusted by age, sex, and collection center. Independence of the <i>APOE</i> promoter polymorphisms was tested by stratification for <i>APOE</i>-ε4 and tertile design was used for age stratification. <b><i><i>Results:</i></i></b> The independence of the −491 AA genotype was observed in the whole sample whereas the independence of the −219 TT genotype was observed only in the oldest population. <b><i><i>Conclusion:</i></i></b> The −491 and −219 <i>APOE</i> promoter polymorphisms incur risk for AD in addition to risk associated with the <i>APOE</i>-ε4 allele, with age accentuating the effect of the −219 TT genotype. Because these polymorphisms appear to influence apoE levels, these results suggest that <i>APOE</i> expression is an important determinant of AD pathogenesis.