Genetic variability at the amyloid-beta precursor protein locus may contribute to the risk of late-onset Alzheimer's disease

In a series of sibpairs with late onset Alzheimer's disease, we have examin ed the segregation of the loci involved in the early onset, autosomal domin ant form of the disorder by using flanking microsatellite repeat markers: t hus we have used APP-PCR3 and D21S210 to examine the segregation of the amy loid-beta precursor protein (APP) gene, the markers DI 4S77 and D14S284 to examine the segregation of the presenilin 1 (PSI) gene and the markers D1S2 27, D1S249 and D1S419 to examine the segregation of presenilin 2 (PS2). We carried out our analyses on the whole dataset of 291 affected sibpairs, and on subsets comprising those sibpairs in which neither had an apolipoprotei n E4 allele (65 affected sibpairs) and those in which both had an apolipopr otein E4 allele (165 affected sibpairs). We used the programs SPLINK to gen erate allele frequencies and MAPMAKER/SIBS to analyze our results. We exami ned the segregation of the markers D19S908 and D19S918 that are close to th e apolipoprotein E (ApoE) gene as a positive control to assess whether the methods we are employing have the capability to identify known loci. The si bpair approach to the identification of genetic risk loci is relatively ins ensitive as indicated by the failure of the ApoE locus to reach statistical significance (P = 0.06). Nevertheless, these data suggest that neither the PS1 nor the PS2 gene is a major locus for late-onset AD, but th at the APP gene can not be ruled out as a risk locus in those sibships without an E4 allele (P = 0.014). The possibility that APP is indeed a locus for late ons et disease will need confirmation in other series of familial cases. (C) 19 99 Elsevier Science Ireland Ltd. All rights reserved.