Abstract
Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD) represent two distinct clinical entities belonging to a wider group, generically named as conformational disorders that share common pathophysiologic mechanisms. It is well-established that the APOE ε4 allele and homozygosity at polymorphic codon 129 in the PRNP gene are the major genetic risk factors for AD and human prion diseases, respectively. However, the roles of PRNP in AD, and APOE in CJD are controversial. In this work, we investigated for the first time, APOE and PRNP genotypes simultaneously in 474 AD and 175 sporadic CJD (sCJD) patients compared to a common control population of 335 subjects. Differences in genotype distribution between patients and control subjects were studied by logistic regression analysis using age and gender as covariates. The effect size of risk association and synergy factors were calculated using the logistic odds ratio estimates. Our data confirmed that the presence of APOE ε4 allele is associated with a higher risk of developing AD, while homozygosity at PRNP gene constitutes a risk for sCJD. Opposite, we found no association for PRNP with AD, nor for APOE with sCJD. Interestingly, when AD and sCJD patients were stratified according to their respective main risk genes (APOE for AD, and PRNP for sCJD), we found statistically significant associations for the other gene in those strata at higher previous risk. Synergy factor analysis showed a synergistic age-dependent interaction between APOE and PRNP in both AD (SF = 3.59, p = 0.027), and sCJD (SF = 7.26, p = 0.005). We propose that this statistical epistasis can partially explain divergent data from different association studies. Moreover, these results suggest that the genetic interaction between APOE and PRNP may have a biological correlate that is indicative of shared neurodegenerative pathways involved in AD and sCJD.
Highlights
Both Alzheimer’s disease (AD) and Creutzfeldt-Jakob disease (CJD) are brain amyloidoses associated with old age
Similar to the results with the APOE e4 allele carriers, when this analysis was performed in the 3 different strata defined by PRNP codon 129, we found a tendency to higher protection associated with the presence of PRNP V129 alleles (M129M: odds ratio (OR) = 0.61, 95% confidence intervals (CIs): 0.28–1.31, p = 0.20; and M129V: OR = 0.55, 95% CI: 0.25– 1.21, p = 0.14; and V129V: OR = 0.25, 95% CI: 0.07–0.91, p = 0.036)
While the potential interaction between APOE and PRNP has been studied in AD populations, yielding controversial results [9,11,14,16,33,34], few reports on the potential interaction between APOE and PRNP in sporadic CJD (sCJD) have been published [24,27]
Summary
Both Alzheimer’s disease (AD) and Creutzfeldt-Jakob disease (CJD) are brain amyloidoses associated with old age. They represent two distinct clinical entities, AD and CJD are considered as part of a wider group generically named as conformational disorders, and brain amyloidosis. These two disorders share common pathophysiologic mechanisms involving protein deposits in the brain due to the conversion of a soluble, normal protein into an insoluble, aggregated form leading to fatal degeneration [1,2,3,4,5]. The role of APOE in CJD and PRNP in AD is matter of discussion
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