In two recent studies from Germany, a strong association was found between the allelic variant T of the amino acid substitution encoding polymorphism 224 C/T (A38V) in exon 2 of the cathepsin D gene (CTSD) and late onset Alzheimer disease (AD). Other studies from Europe and the USA revealed ambiguous results. Therefore, we performed an independent association study on CTSD and AD in a sample of 324 Caucasian patients from Germany, Switzerland, and Italy with late onset AD, and 302 non-demented controls. We could not confirm an association between CTSD genotype and AD, although there was a slight but not significant increase in frequency of the T allele and T carrier status in AD. Post hoc data analyses suggested that there might be a stronger effect of CTSD genotype on AD risk in males, and an interaction between CTSD and APOE genotypes in males but not females. © 2001 Wiley-Liss, Inc.