Ddh299 2885..2892

The 14 haplotype of APOE is the only undisputed genetic risk factor for late-onset Alzheimer’s disease (LOAD). It has been proposed that at least two other polymorphisms in the promoter of the APOE gene (2219G>T and 2491A>T) might also contribute to disease susceptibility, and modulate the impact of structural changes in the ApoE protein, by altering its expression. In order to assess the extent of cisacting influences on APOE expression in human brain, highly quantitative measures of allele discrimination were applied to cortical RNA from individuals heterozygous for the epsilon alleles. A small, but significant, increase in the expression of 14 allele was observed relative to that of the 13 and 12 alleles (P < 0.0001). Similar differences were observed in brain tissue from confirmed LOAD subjects, and between cortical regions BA10 (frontopolar) and BA20 (inferior temporal). Stratification of 14/13 allelic expression ratios according to heterozygosity for the 2219G>T promoter polymorphism revealed significantly lower relative expression of haplotypes containing the 2219T allele (P 5 0.02). Our data indicate that, in human brain, most of the cis-acting variance in APOE expression is accounted for by the 14 haplotype, but there are additional, small, cis-acting influences associated with promoter genotype.