The cathepsin D (224C/T) polymorphism confers an increased risk to develop Alzheimer's disease in men.

The lysosomal protease cathepsin D is likely involved in beta-amyloidogenesis in Alzheimer's disease (AD). There is evidence for a single nucleotide polymorphism (rs17571) of the cathepsin D gene to be associated with increased AD risk. However, little is known about gender-specific differences. Therefore, we performed a genetic association study focusing on gender-specific differences in 434 participants (219 AD and 215 controls). Screening of the rs17571 shows a significantly higher proportion of T-allele carriers among male Alzheimer patients (28.5%) when compared with male controls (13.8%, p = .013, p(corr) = .039). The odds ratio was 2.48 (95% confidence interval: 1.14-5.58). There was no significant difference in the T-allele distribution in women. Including APOE4 status and age did not have an additional effect on the morbidity risk. Thus, our results support the idea that rs17571 confers an increased risk for AD in men but not in women. Further investigation should substantiate the role of gender for AD risk of rs17571.

[1]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease: Report of the NINCDS—ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease , 2011, Neurology.

[2]  Nikolaos A Patsopoulos,et al.  Claims of sex differences: an empirical assessment in genetic associations. , 2007, JAMA.

[3]  K. Blennow,et al.  The Cathepsin D rs17571 polymorphism: effects on CSF tau concentrations in Alzheimer disease , 2006, Human mutation.

[4]  Kaj Blennow,et al.  Towards compendia of negative genetic association studies: an example for Alzheimer disease , 2006, Human Genetics.

[5]  A. Ariza,et al.  Age at Onset: An Essential Variable for the Definition of Genetic Risk Factors for Sporadic Alzheimer's Disease , 2005, Annals of the New York Academy of Sciences.

[6]  D. Y. Lee,et al.  Lack of association of cathepsin D genetic polymorphism with Alzheimer's disease in Koreans. , 2005, Archives of gerontology and geriatrics.

[7]  F. Panza,et al.  The cathepsin D gene exon 2 (C224T) polymorphism and sporadic Alzheimer's disease in European populations. , 2005, The journals of gerontology. Series A, Biological sciences and medical sciences.

[8]  E. Zocchi,et al.  Autocrine and Paracrine Calcium Signaling by the CD38/NAD+/Cyclic ADP‐Ribose System , 2004, Annals of the New York Academy of Sciences.

[9]  Zhenxin Zhang,et al.  Association between Cathepsin D Polymorphism and Alzheimer’s Disease in a Chinese Han Population , 2004, Dementia and Geriatric Cognitive Disorders.

[10]  W. Maier,et al.  Putative association of polymorphism in the mannose 6-phosphate receptor gene with major depression and Alzheimer's disease , 2004, Psychiatric genetics.

[11]  Christian Haass,et al.  Games Played by Rogue Proteins in Prion Disorders and Alzheimer's Disease , 2003, Science.

[12]  M. Catani,et al.  Cathepsin D Polymorphism in Italian Elderly Subjects with Sporadic Late-Onset Alzheimer’s Disease , 2003, Dementia and Geriatric Cognitive Disorders.

[13]  A. Pfeffer,et al.  Simultaneous analysis of five genetic risk factors in Polish patients with Alzheimer's disease , 2003, Neuroscience Letters.

[14]  S. Sorbi,et al.  Cathepsin D polymorphism in Italian sporadic and familial Alzheimer's disease , 2002, Neuroscience Letters.

[15]  W. Maier,et al.  Cathepsin D: screening for new polymorphisms using single-strand conformation polymorphism analysis. , 2002, International journal of molecular medicine.

[16]  O. Combarros,et al.  Lack of association between cathepsin D genetic polymorphism and Alzheimer disease in a Spanish sample. , 2002, American journal of medical genetics.

[17]  L. Feuk,et al.  SNP association studies in Alzheimer's disease highlight problems for complex disease analysis. , 2001, Trends in genetics : TIG.

[18]  L. Feuk,et al.  Lack of replication of association findings in complex disease: an analysis of 15 polymorphisms in prior candidate genes for sporadic Alzheimer's disease , 2001, European Journal of Human Genetics.

[19]  H. Arai,et al.  Cathepsin D polymorphism not associated with Alzheimer's disease in Japanese , 2001, Annals of neurology.

[20]  R. Nitsch,et al.  Non-replication of association between cathepsin D genotype and late onset Alzheimer disease. , 2001, American journal of medical genetics.

[21]  M. McInnis,et al.  No evidence for genetic association or linkage of the cathepsin D (CTSD) exon 2 polymorphism and Alzheimer disease , 2001, Annals of neurology.

[22]  M. McInnis,et al.  Candidate genes showing no evidence for association or linkage with Alzheimer's disease using family-based methodologies , 2000, Experimental Gerontology.

[23]  S. Sevush,et al.  The genetic association between Cathepsin D and Alzheimer's disease , 2000, Neuroscience Letters.

[24]  S. DeKosky,et al.  Genetic polymorphisms in the cathespin D and interleukin-6 genes and the risk of Alzheimer's disease , 2000, Neuroscience Letters.

[25]  J. Pauls,et al.  A genetic variation of cathepsin D is a major risk factor for Alzheimer's disease , 2000, Annals of neurology.

[26]  S. McIlroy,et al.  Cathepsin D gene exon 2 polymorphism and sporadic Alzheimer's disease , 1999, Neuroscience Letters.

[27]  F. Jessen,et al.  Genetic polymorphism of cathepsin D is strongly associated with the risk for developing sporadic Alzheimer's disease , 1999, Neuroscience Letters.

[28]  G. Lynch,et al.  β-Amyloid increases cathepsin D levels in hippocampus , 1998, Neuroscience Letters.

[29]  J. Haines,et al.  Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. , 1997, JAMA.

[30]  J. Haines,et al.  Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-analysis , 1997 .

[31]  U Seligsohn,et al.  Improved method for genotyping apolipoprotein E polymorphisms by a PCR-based assay simultaneously utilizing two distinct restriction enzymes. , 1997, Clinical chemistry.

[32]  Jinhe Li,et al.  Gene expression and cellular content of cathepsin D in Alzheimer's disease brain: Evidence for early up-regulation of the endosomal-lysosomal system , 1995, Neuron.

[33]  R. Nixon,et al.  The Lysosomal System in Neurons , 1992 .

[34]  M. Takeda,et al.  Abnormal distribution of cathepsins in the brain of patients with Alzheimer's disease , 1991, Neuroscience Letters.

[35]  E. Bird,et al.  Lysosomal proteinase antigens are prominently localized within senile plaques of Alzheimer's disease: evidence for a neuronal origin , 1990, Brain Research.

[36]  M. Mattei,et al.  Cloning and sequencing of the 52K cathepsin D complementary deoxyribonucleic acid of MCF7 breast cancer cells and mapping on chromosome 11. , 1988, Molecular endocrinology.

[37]  J. Kay,et al.  Immunolocalization of cathepsin D in normal and neoplastic human tissues. , 1986, Journal of clinical pathology.

[38]  Nick C Fox,et al.  Letter abstract - Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's Disease , 2009 .

[39]  D. Blacker,et al.  Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database , 2007, Nature Genetics.

[40]  G. Lynch,et al.  Beta-amyloid increases cathepsin D levels in hippocampus. , 1998, Neuroscience letters.

[41]  I. Touitou,et al.  Missense polymorphism (C/T224) in the human cathepsin D pro-fragment determined by polymerase chain reaction--single strand conformational polymorphism analysis and possible consequences in cancer cells. , 1994, European journal of cancer.

[42]  M A Pericak-Vance,et al.  Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. , 1993, Neurology.

[43]  R. Nixon,et al.  The lysosomal system in neurons. Involvement at multiple stages of Alzheimer's disease pathogenesis. , 1992, Annals of the New York Academy of Sciences.

[44]  R. Nixon,et al.  Proteases and Protease Inhibitors in Alzheimer's Disease Pathogenesis. Proceedings of a conference. Bethesda, Maryland, December 16-18, 1991. , 1992, Annals of the New York Academy of Sciences.

[45]  F. Ballard,et al.  Lysosomes : their role in protein breakdown , 1987 .