No evidence for genetic association or linkage of the cathepsin D (CTSD) exon 2 polymorphism and Alzheimer disease

Two recent case-control studies have suggested a strong association of a mi ssense polymorphism in exon 2 of the cathepsin D gene (CTSD) and Alzheimer disease (AD). However, these findings were not confirmed in another indepen dent study. We analyzed this polymorphism in two large and independent AD s tudy populations and did not detect an association between CTSD and AD. The first sample was family-based and included 436 subjects from 134 sibships discordant for AD that were analyzed using the sibship disequilibrium test (SDT, p 0.68) and the sib transmission/disequilibrium test (Sib-TDT, p = 0. 81). The second sample of 200 AD cases and 182 cognitively normal controls also failed to show significant differences in the allele or genotype distr ibution in cases versus controls (X-2, p = 0.91 and p = 0.88, respectively) . In addition, two-point linkage analyses in an enlarged family sample (n = 670) did not show evidence for linkage of the chromosomal region around CT SD. Thus, our analyses on more than 800 subjects suggest that if an associa tion between the CTSD exon 2 polymorphism and AD exists, it is likely to be smaller than previously reported.