We have found an APOE epsilon 4 allelic frequency of 0.289 (95% CI 0.195-0.383) in Spanish AD patients (n = 88; average age = 71.2 +/- 9.37) and of 0.061 (95% CI 0.023-0.099) in age-matched controls (n = 147; average age = 71.5 +/- 10.29). Remarkably no ApoE 4/4 subjects were observed in any of the age-matched control groups compared to a total of 22 AD patients with the ApoE 4/4 phenotype. The combined odds ratio for subjects with one or two epsilon 4 alleles in the present study is 6.25 (95% CI 3.13-12.60), which is one of the highest so far reported. Altogether our results suggest a trans-European difference in the ApoE epsilon 4 frequency but no differences in the strength of the association between APOE4 and AD.