A genetic variation of cathepsin D is a major risk factor for Alzheimer's disease

Cathepsin D (catD) is an intracellular acid protease possibly involved in A lzheimer's disease (AD)-related neurodegeneration through cleavage of amylo id precursor protein into amyloidogenic components. We studied whether an e xonic polymorphism of the catD gene (C --> T [Ala --> Val] transition at po sition 224), which possibly influences pro-catD secretion and intracellular maturation of the enzyme, was associated with the risk for the development of AD in 127 demented patients and 184 controls. The catD*T allele was sig nificantly overrepresented in demented patients (11.8%) compared with nonde mented controls (4.9%). Carriers of the catD*T allele had a 3.1-fold increa sed risk for developing AD than noncarriers. Carriers of the apolipoprotein E (ApoE) epsilon 4 allele (ApoE*4) had a 3.9-fold increased risk than non- carriers. The adjusted odds ratio for subjects with the ApoE*4 and the catD *T allele was 19.0 compared with subjects with neither of these two alleles . Our data confirm the results of a recently performed pilot study in an in dependent sample and suggest that the catD genotype is strongly associated with the risk for AD.