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AD etiology has been studied by many groups, but since the discovery of the <jats:italic>APOE<\/jats:italic> \u03b54 allele, no further genes have been mapped conclusively to late\u2010onset AD (LOAD). In this study, we examined genetic association with LOAD susceptibility in 738 Caucasian families (4,704 individuals) and an independent case\u2013control dataset with 296 cases and 566 controls exploring 11 candidate genes (47 SNPs common to both samples). In addition to tests for main effects and haplotypes, the MDR\u2010PDT was used to search for gene\u2013gene interactions in the family data. We observed significant haplotype effects in <jats:italic>ACE<\/jats:italic> in family and case\u2013control samples using standard and cladistic haplotype models. <jats:italic>ACE<\/jats:italic> was also part of significant 2 and 3\u2010locus MDR\u2010PDT joint effects models with Alpha\u20102\u2010Macroglobulin (<jats:italic>A2M<\/jats:italic>), which mediates the clearance of A\u03b2, and Leucine\u2010Rich Repeat Transmembrane\u20103 (<jats:italic>LRRTM3<\/jats:italic>), a nested gene in Alpha\u20103 Catenin (<jats:italic>CTNNA3<\/jats:italic>) which binds Presenilin\u20101. This result did not replicate in the case\u2013control sample, and may not be a true positive. These genes are related to A\u03b2 clearance; thus this constellation of effects might constitute an axis of susceptibility for LOAD. The consistent <jats:italic>ACE<\/jats:italic> haplotype result between independent family\u2010based and unrelated case\u2013control datasets is strong evidence in favor of <jats:italic>ACE<\/jats:italic> as a susceptibility locus for AD, and replicates results from several other studies in a large sample. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ajmg.b.30899","type":"journal-article","created":{"date-parts":[[2008,12,22]],"date-time":"2008-12-22T20:43:05Z","timestamp":1229978585000},"page":"721-735","source":"Crossref","is-referenced-by-count":30,"title":["An association analysis of Alzheimer disease candidate genes detects an ancestral risk haplotype clade in <i>ACE<\/i> and putative multilocus association between <i>ACE<\/i>, <i>A2M<\/i>, and <i>LRRTM3<\/i>"],"prefix":"10.1002","volume":"150B","author":[{"given":"Todd 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