Preferential deposition of amyloid beta protein (Abeta) in the form Abeta40 in Alzheimer's disease is associated with a gene dosage effect of the apolipoprotein E E4 allele.
The effect of apolipoprotein E (ApoE) genotype on the deposition of amyloid beta protein (Abeta) was examined in 54 patients with Alzheimer's disease. No difference in the amount of Abeta deposited as Abeta42(43) was seen between genotype groups with no, one or two E4 alleles. However, the amount of Abeta40 deposited increased according to the copy number of E4 alleles with patients possessing one E4 allele containing more than twice, and those with two E4 alleles, four times, the amount of Abeta40 in their brains compared to patients without an E4 allele. The increase in total Abeta deposited within the tissue (i.e. Abeta40 plus Abeta42(43) loads) in the presence of an E4 allele is therefore due entirely to an enhanced deposition of Abeta40. These data are consistent with the suggestion that the presence of E4 within pre-existing Abeta42(43) containing plaques may lower the threshold to fibrilization of Abeta40 thereby promoting its subsequent deposition. Thus, although the total amount of Abeta initially deposited in the brain as Abeta42(43) is not affected by the binding of any one particular ApoE isoform this does influence the subsequent maturation of plaques with a greater proportion transforming into Abeta40 containing cored plaques when the E4 isoform is present.
Mann
D M
DM
Department of Pathological Sciences, Division of Molecular Pathology, University of Manchester, UK.
Iwatsubo
T
T
Pickering-Brown
S M
SM
Owen
F
F
Saido
T C
TC
Perry
R H
RH
D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism*; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000096:biosynthesis* / Q000235:genetics*; D001923:Brain Chemistry / Q000235:genetics* / Q000502:physiology*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)