ApoE ϵ3‐haplotype modulates Alzheimer beta‐amyloid deposition in the brain

Abstract

ApoE epsilon4 allele increases the risk of late-onset Alzheimer disease (AD) as well as the amount of beta-amyloid deposition in the brain. Because half of AD patients do not have ApoE epsilon4, it is important to search for other determinants of ApoE that modify AD risk. We tested whether the haplotype background of the most common ApoE allele, epsilon3, influences brain amyloid deposition or the risk of neuropathologically verified AD in a population-based sample of elderly Finns. To exclude the effects of ApoE protein polymorphism we focused these analyses on subjects homozygous for epsilon3. Haplotypes were defined using polymorphisms at positions - 491 and -219 of the ApoE promoter and at position +113 of intron-1. We found that epsilon3-haplotypes containing the promoter allele -219T were associated with reduced amyloid deposition and reduced risk of neuropathologically verified AD as compared to epsilon3-haplotypes containing -219G. The functional polymorphism(s) responsible for the haplotypic difference remains to be identified. These results indicate that there is significant allelic variation in the ApoE gene region, which modulates brain amyloid deposition and AD risk, independent of the ApoE protein polymorphism.

The complex interaction between APOE promoter and AD: an Italian case–control study

“…However, as observed in these two studies, the positive association between rs769446 and AD shows contrasting results on the possible allele (T or C) conferring a higher AD risk. The analysis of the distribution of the genotypic and estimated allelic frequencies of rs405509 showed an overrepresentation of G/G genotype and the G allele in AD patients according to Myllykangas et al 36 At variance, our results are in contrast with those carried out on French population 9,22 reporting an increased frequency of the T À219 allele in AD patients. The same results were obtained in elderly AD subjects as reported in a recent meta-analysis 26 and in other studies on population-based cohort.…”

Relations of APOE promoter polymorphisms to LDL cholesterol and markers of subclinical atherosclerosis in young adults

“…The frequencies of the 2219G and 2219T alleles were 0.62 and 0.38, respectively, and those of the 1113G and 1113C alleles were 0.63 and 0.37. The promoter genotype distributions were in Hardy-Weinberg equilibrium and similar to those seen in previous Finnish studies (1,17,18). Age, BMI, systolic or diastolic blood pressure, and smoking did not differ significantly between the APOE promoter genotype groups in the e3/e3 carriers ( Tables 1, 2).…”

Chromosome 21 BACE2 haplotype associates with Alzheimer's disease: A two-stage study

“…Because also APOE q2 bears an impact on Ahload, in addition to q4 [12], we made a further analysis of Ah-load in the q3/q3 subgroup. This is a more standardized group than the APOE q4-negatives and excludes the impact of both q2 and q4 [14]. In the q3/q3 subgroup an even stronger association between BACE2 = exon-6 SNP and Ah load was found ( p = 0.001) (Fig.…”