Candidate genes showing no evidence for association or linkage with Alzheimer's disease using family-based methodologies

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorde r. To date, a large number of candidate genes have been associated with the disease, however none of these findings has been consistently replicated i n independent datasets. In this study we report the results of family-based analyses for polymorphisms of five such candidates on chromosomes 2 (inter leukin-1 beta, IL-1B), 3 (butyrylcholinesterase, BCHE), 11 (cathepsin D, CT SD; Fe65, APBB1) and 12 (lipoprotein receptor-related protein-1, LRP1) that were all suggested to be associated with AD in recent case-control studies . To minimize the possibility of spurious findings due to population admixt ure, we used a family-based design applying the sibship disequilibrium test (SDT) as well as two-point parametric linkage analyses on families from th e National Institute of Mental Health (NIMH) Genetics initiative. Contrary to the initial reports, none of the polymorphisms that were analyzed showed evidence for association or linkage with AD in our families. Our results s uggest that the previously reported associations from case-control studies are either (a) false positive results, e.g. due to type I error or populati on admixture, (b) smaller than initially proposed, or (c) due to linkage di sequilibrium with an as yet unidentified polymorphism nearby. (C) 2000 Else vier Science Inc. All rights reserved.