The genetic association between Cathepsin D and Alzheimer's disease F.C. Crawford a,1 , M.J. Freeman a,1, * , J. Schinka a , L.I. Abdullah a , D. Richards a , S. Sevush b , R. Duara c , M.J. Mullan a a Roskamp Institute and the University of South Florida Memory Disorder Clinic, 3515 E. Fletcher Avenue, Tampa, FL 33613, USA b University of Miami Memory Disorder Clinic, Miami, FL 33136, USA c Mount Sinai Memory Disorder Clinic, Miami, FL 33140, USA Received 3 May 2000; received in revised form 30 May 2000; accepted 30 May 2000 Abstract The aspartyl protease Cathepsin D has previously been suggested to play a role in the Alzheimer's disease (AD) process because of its ability to cleave the b-amyloid precursor protein and the possibility that it may be one of the `secretase' enzymes. A functional C ) T polymorphism in the Cathepsin D gene (CATD) has been reported to be asso- ciated with increased risk for AD in Caucasian case-control studies; speci®cally, the T-carrying genotypes confer increased risk. We have examined this association in our own Caucasian dataset of 210 AD cases and 120 controls, and in an additional Hispanic dataset comprising 79 AD cases and 112 controls. In Hispanics we ®nd a modest interaction between CATD genotype and age of onset on risk for AD, such that the non-T-carrying genotype confers increased risk. In our Caucasian dataset we ®nd no evidence for association between the CATD polymorphism and AD, although we do observe a small tendency towards an increase in the T-carrying genotypes in the case group, consistent with previous studies. We conducted an aggregate analysis of the published Caucasian datasets and found evidence that this CATD polymorphism (or another locus in linkage disequilibrium) does contribute signi®cant, but small (,2%) risk for AD. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Alzheimer's disease; Cathepsin D; b-Amyloid precursor protein The `secretase' enzymes responsible for cleavage of the b-amyloid precursor protein (bAPP) into amyloidogenic or non-amyloidogenic fragments have emerged as prime targets for therapeutic intervention in the Alzheimer's disease (AD) process. The observed properties of these enzymes have suggested them to be aspartyl proteases [5,11,23], and consequently the aspartyl protease Cathepsin D (CatD) has been investigated as a possible secretase candidate. CatD demonstrates in vitro properties consistent with the b-secretase, (which cleaves the N terminal of the b- amyloid peptide (Ab) from bAPP), including enhanced cleavage of peptide containing the `Swedish' mutation which led to the suggestion that CatD could be the b-secre- tase [3,5,12]. However, although CatD ful®lls the amyloi- dogenic processing requirements of the b-secretase, data from transgenic mice with a knockout of the CatD gene (CATD) demonstrate that CatD is not essential for amyloi- dogenic processing [18]. Furthermore, a b-site APP Cleav- ing Enzyme (BACE) which meets the criteria expected of the b-secretase has recently been identi®ed by four indepen- dent groups [9,19,21,24]. Exclusion of CatD from being the b-secretase does not preclude its involvement in the pathogenesis of AD, as g- secretase-like properties have also been demonstrated [17,23]. For instance, several di¯uoro ketones that inhibit Ab production at the g-secretase level have the ability to block CatD activity [23]. Furthermore, using a synthetic peptide encompassing the g-secretase site, in vitro studies have shown cleavage by CatD at the amyloidogenic sites (after A1a42 or after Thr43) to release the carboxyl termini of Ab; this activity was increased at acidic pH and inhibited by pepstatin [6]. Cathepsin D has also been shown to hydro- lyze Ab between Phe 19 and Phe 20 (close to the a-secretase site), and the presence of the bAPP codon 692 mutation (Gly 21 ) opposes this effect [8]. Neuroscience Letters 289 (2000) 61±65 0304-3940/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(00)01260-X www.elsevier.com/locate/neulet * Corresponding author. Tel.: 11-813-974-3722; fax: 11-813 974 3915. E-mail address: mfreeman@chuma.cas.usf.edu (M.J. Freeman). 1 These authors contributed equally to this work.