Cathepsin D polymorphism in Italian sporadic and familial Alzheimer’s disease Silvia Bagnoli a , Benedetta Nacmias a , Andrea Tedde a , Bianca Maria Guarnieri b , Elena Cellini a , Monica Ciantelli a , Concetta Petruzzi b , Antonella Bartoli b , Luigi Ortenzi b , Antonio Serio b , Sandro Sorbi a, * a Department of Neurological and Psychiatric Sciences, University of Florence, Viale Morgagni 85, 50134 Florence, Italy b Casa di Cura “Villa Serena”, Associazione L. Petruzzi, Citta ` Sant Angelo, Pescara, Italy Received 23 January 2001; received in revised form 30 April 2002; accepted 15 May 2002 Abstract A recent study has shown that a genetic variation in the Cathepsin D (catD) gene is a major risk factor for the devel- opment of Alzheimer’s disease (AD). CatD is an intracellular aspartyl protease involved in neurodegeneration. A C ! T (Ala ! Val) transition at position 224 has been associated with altered intracellular maturation. Recently, a significant overrepresentation of the T allele of the catD gene in AD patients compared with controls was reported. However, this finding has not yet been confirmed. We analyzed the distribution of catD and apolipoprotein E polymorphisms in Italian patients with sporadic and familial AD (FAD). Our studies revealed that the distribution of catD polymorphism did not differ in AD and FAD patients and controls. Thus, our data do not support a role for the catD gene as a genetic risk factor in the development of AD. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Alzheimer’s disease; Cathepsin D; Genetics; Apolipoprotein E; Polymorphism Alzheimer’s disease (AD) is a devastating neurodegen- erative disorder and a genetically complex multi-factorial disease involving several candidate genes. Three of these genes have been implicated in familial AD (FAD), namely the amyloid precursor protein (APP), the presenilin 1 (PS-1) and presenilin 2 genes [10]. Mutations in these genes account for the majority of FAD cases; however, this form is responsible for the development of the disease in less than 1% of all AD patients. Moreover, the apolipoprotein E (ApoE) 14 allele and interleukin-1 are the only genetic factors consistently implicated in AD, which are neither necessary nor sufficient for the develop- ment of the disease [9,18]. The search for other genetic factors has shown that polymorphism in the PS-1, the protease inhibitor a 1 -antichimotrypsin, butyrylcholinester- ase, the estrogen receptor a (ESR1), the low density lipo- protein receptor-related protein, a2-macroglobulin, the angiotensin converting enzyme, nitric oxide synthase, bleo- mycin hydrolase, methylenetetrahydrofolate reductase, the tumor necrosis factor receptor superfamily member 6 and the ESR1 could be involved in the pathogenesis of AD, interfering with b-amyloid deposition [16]. Recently, the ‘secretase’ enzymes responsible for cleavage of the APP into amyloidogenic or non-amyloidogenic fragments have been involved in the pathogenesis of AD. Cathepsin D (catD) is an intracellular aspartyl protease which exhibits b- and g-secretase-like activity in vitro [5,6,12]. In 1994, Touiton and colleagues identified a single nucleotide poly- morphism (C to T) at position 224 in exon 2 [20], predicting an exchange of Ala38 to Val in the catD pro-fragment, which might alter secretion or intracellular maturation of pro-catD [4]. A recent study [15] shows that catD is a genetic risk factor for AD, with the catD T allele being significantly overrepresented in AD patients, compared with non-demen- ted controls. According to this study, a combination of ApoE 14 and catD T alleles further increases the risk of developing AD. However, other studies have not been able to replicate these results and it has been suggested that the effect of the catD gene on susceptibility may be limited to certain populations or families [2,7,11,13,16]. In light of these contrasting findings, we investigated the segregation of catD Ala224Val and ApoE polymorphisms in Neuroscience Letters 328 (2002) 273–276 0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(02)00547-5 www.elsevier.com/locate/neulet * Corresponding author. Tel.: 139-55-4298-465; fax: 139-55- 4271-380. E-mail address: sorbi@unifi.it (S. Sorbi).