PREFERENTIAL DEPOSITION OF AMYLOID-BETA PROTEIN (A-BETA) IN THE FORM A-BETA(40) IN ALZHEIMERS-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 am yloid 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 allele s. However, the amount of A beta(40) deposited increased according to the copy number of E4 alleles with patients possessing one E4 allele c ontaining 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(4 0). These data are consistent with the suggestion that the presence of E4 within pre-existing A beta(42(43)) containing plaques may lower th e threshold to fibrilization of A beta(40) thereby promoting its subse quent deposition. Thus, although the total amount of A beta initially deposited in the brain as A beta(42(43)) is not affected by the bindin g of any one particular ApoE isoform this does influence the subsequen t 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.