Chromosome 21 BACE2 haplotype associates with Alzheimer's disease:: A two-stage study

Genetic linkage studies have provided evidence for a late-onset Alzheimer's disease (AD) susceptibility locus on chromosome 21q. We have tested, in a two-stage association study, whether allelic or haplotype variation of the beta-amyloid cleaving enzyme-2 (BACE2) locus on chromosome 21q affects the risk of late-onset AD. In stage-1, an unselected population-based sample of Finns aged 85 years or over (n = 515) was analysed. Neuropathologic examination including beta-amyloid load quantification was possible in over 50% (n = 264) of these subjects. AD patients (n = 100) and controls (n = 48) were defined by modified neuropathological NIA-RI criteria. Positive associations were taken as a hypothesis, and tested in stage-2 using 483 AD families from the USA. Four single nucleotide polymorphisms (SNPs) of BACE2 gene were tested in stage-1. A SNP close to exon-6 was associated with neuropathologically verified AD (p = 0.02) and also with beta-amyloid load in non-selected autopsied subjects after conditioning with APOE genotype (p=0.001). In haplotype analysis a specific, relatively common haplotype (H5) was found to associate with AD (p=0.004) and a second haplotype (H7) showed a weaker association with protection against AD (p = 0.04). In stage-2, the SNP association was not replicated, whereas the haplotype H5 association was replicated (p = 0.004) and a trend to association was found with the putative protective haplotype H7 (two-sided p = 0.08). BACE2 haplotype association with AD in two independent datasets provides further evidence for an AD susceptibility locus on chromosome 21q within or close to BACE2. (c) 2005 Elsevier B.V. All rights reserved.