Taking it together, we found numerous aspects of PrP proteinopathy that were significantly enhanced in the presence of the ε4 allele including elevated levels of the total PrP, PrPSc, detergent insoluble PrP, enhanced PrP oligomerization and evidence of increased complexing of pathologically altered PrP with apoE, which constitute one important mechanism, through which the ε4 allele negatively affects the outcome of prion disease. The gene discussed is PRNP; the disease is prion disease.