Phenotypes of apolipoprotein E (apo E) were determined by the iso-electric focusing method in 42 Japanese patients with nonfamilial late-onset Alzheimer's disease (AD) and 96 age-matched controls without hyperlipidemia and/or diabetes. There was a striking difference in the distribution of apo E phenotypes between patients with AD and controls (P < 0.0001). Such a difference was mostly attributable to different frequencies of phenotypes E4/3 and E3/3. The apo E4/3 phenotype was detected in 24 (57.1%) of 42 patients with AD, more than six times oftener than in nine (9.4%) of 96 controls. In contrast, apo E3/3, which is the most common apo E phenotype in various ethnic groups, was detected in only 15 (35.7%) patients with AD. These results indicate a strong association between apo E4 isoprotein and Japanese late-onset nonfamilial AD, and that apo E4 is a possible risk factor for the development of this type of AD.