Earlier Onset of Alzheimer's Disease: Risk Polymorphisms Within PRNP, PRND, CYP46, and APOE Genes

Article type: Research Article

Authors: Golanska, Ewa^{a; *} | Hulas-Bigoszewska, Krystyna^a | Sieruta, Monika^a | Zawlik, Izabela^a | Witusik, Monika^a | Gresner, Sylwia M.^a | Sobow, Tomasz^b | Styczynska, Maria^c | Peplonska, Beata^c | Barcikowska, Maria^c | Liberski, Pawel P.^a | Corder, Elizabeth H.^d

Affiliations: [a] Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland | [b] Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland | [c] Department of Neurodegenerative Disorders, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland | [d] Matrix Genomics, Inc., Santa Fe, New Mexico, USA

Correspondence: [*] Corresponding author: Ewa Golanska, Department of Molecular Pathology and Neuropathology, Medical University of Lodz, 8/10 Czechoslowacka str., 92-216 Lodz, Poland. Tel.: +48 42 6757611; 6757629; Fax: +48 42 6791477; E-mail: [email protected].

Note: [] Communicated by Eliecer Coto

Abstract: We studied eight polymorphisms within APOE, PRNP, PRND, and CYP46 genes in 213 Polish late-onset patients with Alzheimer's disease (AD) and 171 non-demented elderly controls. A latent classification approach, grade-of-membership analysis, was taken to identify three extreme pure type risk sets defined by the probabilities of being affected with AD and for genotypes found at the examined genes. Sets I and II represented high intrinsic risk, having a higher density of various genotypes compared to set III, at low intrinsic risk. A gradient of onset age depending on membership in the risk sets was also observed. Logistic regression analysis showed that the highest risk for AD was found for individuals who co-inherited APOE ε4 allele, PRNP codon 129 homozygosity, PRND codon 174 Thr allele, and CYP46 rs754203 g allele. AD can be influenced by genetic profiles leading to appearance of the disease, composed of genes which separately evoke a little or unnoticeable effect. Moreover, there may be multiple sufficient risk sets for AD. Looking at multiple genes together rather than analyzing them individually, may improve identification of risk alleles.

Keywords: Alzheimer's disease, APOE, CYP46, genetic polymorphisms, grade-of-membership analysis, multiple genetic risk factors, PRND, PRNP

DOI: 10.3233/JAD-2009-1055

Journal: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 359-368, 2009