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

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 epsilon4 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.

Genetic Cross-Interaction between APOE and PRNP in Sporadic Alzheimer's and Creutzfeldt-Jakob Diseases

“…Of special relevance for this work, it is the study by Combarros and collaborators [12]; where opposite to our results, they did not find any association for the PRNP gene with the risk of developing AD, even after stratifying by APOE ε4 allele status in a Spanish population. Taking into account that even in our study the association effect is small; this discrepancy may be explained by the different geographic distribution of the studied populations that may play an important role in the interpretation of the results [16], [45], [76]. Thus, although both populations are of Spanish origin, Combarros' population is restricted to North of Spain, while ours have been recruited mainly from two different Spanish geographical areas (Eastern and Central areas).…”

Parkinson's Disease and Low Frequency Alleles Found Together Throughout LRRK2

“…Information on genotype/diplotype for these blocks identified three patterns of risk represented by GoM groups (I, II, and III). GoM has been employed in a similar way to reduce complex data to a tractable number of patterns in previous medical and genetic studies – to define subtypes of disease and patterns of disease progression, endophenotypes, genetic risk sets for disease, and as a form of sibpair linkage analysis having apparently high statistical power 11–26 .…”

24S-hydroxycholesterol and cholesterol-24S-hydroxylase (CYP46A1) in the retina: from cholesterol homeostasis to pathophysiology of glaucoma

“…We also analyzed the rs754203 single nucleotide polymorphism (SNP) in cyp46a1 gene in our population. rs754203 SNP has been associated with Alzheimer's disease in some (Fu et al, 2009;Golanska et al, 2009;Li et al, 2006;Papassotiropoulos et al, 2003;Wang et al, 2004) but not all studies (Garcia et al, 2009). Interestingly, glaucoma patients presented higher frequency of the T-allele in cyp46a1 gene compared to control subjects.…”