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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.

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