Apolipoprotein E (ApoE) phenotypes and corresponding allele frequencies were examined in 72 patients (50-90 years of age) with sporadic Alzheimer's disease (AD) and 83 elderly controls (61-96 years of age) in Hokkaido, the northern part of Japan. The frequency of the ApoE-epsilon 4 allele was significantly higher in the patients with either early-onset (age < 65 years) AD (0.40) or late-onset AD (0.26) than in controls (0.07), while the patients developing AD before 50 years of age had no epsilon 4 allele. The mean age at onset of AD was significantly lower in the ApoE-epsilon 4 homozygotes compared to that in the patients with either one or no epsilon 4 allele (60.2, 71.3 and 70.3 years, respectively). Our results indicate that the ApoE-epsilon 4 allele is associated with susceptibility to Japanese sporadic AD developing after 50 years of age and homozygosity for the epsilon 4 allele shifts the onset to earlier age.