Preferential deposition of amyloid beta protein (A beta) in the form A beta(40) 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 (A beta) was examined in 54 patients with Alzheimer's disease. No difference in the amount of A beta deposited as A beta(42(43)) was seen between genotype groups with no, one or two E4 alleles. However, the amount of A beta(40) 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 A beta(40) in their brains compared to patients without an E4 allele. The increase in total A beta deposited within the tissue (i.e. A beta(40) plus A beta(42(43)) loads) in the presence of an E4 allele is therefore due entirely to an enhanced deposition of A beta(40). These data are consistent with the suggestion that the presence of E4 within pre-existing A beta(42(43)) containing plaques may lower the threshold to fibrilization of A beta(40) thereby promoting its subsequent deposition. Thus, although the total amount of A beta initially deposited in the brain as A beta(42(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 A beta(40) containing cored plaques when the E4 isoform is present. (C) 1997 Elsevier Science Ireland Ltd.