ApoE epsilon3-haplotype modulates Alzheimer beta-amyloid deposition in the brain.
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.
Myllykangas
Liisa
L
Department of Pathology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Polvikoski
Tuomo
T
Reunanen
Karoliina
K
Wavrant-De Vrieze
Fabienne
F
Ellis
Clare
C
Hernandez
Dena
D
Sulkava
Raimo
R
Kontula
Kimmo
K
Verkkoniemi
Auli
A
Notkola
Irma-Leena
IL
Hardy
John
J
Perez-Tur
Jordi
J
Haltia
Matti J
MJ
Tienari
Pentti J
PJ
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000235:genetics*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics
D016229:Amyloid beta-Peptides; D053318:Apolipoprotein E3; D001057:Apolipoproteins E