Background: The APOE genotype has been shown to influence the risk of developing sporadic and familial AD. This effect is isoform-dependent, the APOE ε4 allele increasing susceptibility and the APOE ε2 allele providing protection. Amyloid formation is an important part of the pathogenesis in AD as well as in spongiform encephalopathies; apoE deposition in amyloid plaques has been documented in both conditions. Methods: We examined the frequency of the APOE alleles in patients with various forms of transmissible spongiform encephalopathies, or prion diseases, including sporadic and iatrogenic Creutzfeldt-Jakob disease; familial Creutzfeldt-Jakob disease associated with PRNP 178N/129V and 200K/129M point mutations and a 24-nucleotide repeat expansion; fatal familial insomnia caused by the 178N/129M mutation; Gerstmann-Straussler-Scheinker disease associated with 102L/129M mutation; and kuru. Results: None of the groups we studied had a significant excess of APOE ε4 allele when compared with appropriate controls. Conclusion: Our results do not support the contention that the APOE ε4 allele is a risk factor for developing Creutzfeldt-Jakob disease or related disorders.