We examined the apolipoprotein E (ApoE) genotypes of 19 middle-aged non-demented subjects with cerebral amyloid beta protein (Abeta) deposits, and compared the results with those of 16 patients with sporadic Alzheimer's disease (AD) and those of 34 age-matched controls. The frequency of the ApoE epsilon4 allele was higher (P = 0.0256) in these 19 subjects (0.211) than in controls (0.059), and was close to that in AD patients (0.281). This result suggests that middle-aged non-demented subjects with cerebral Abeta deposits are at high risk of developing AD, and that the diffuse Abeta deposits in these cases represent an early stage of AD pathology. We speculate that in the majority of late-onset sporadic AD patients, cerebral Abeta deposition commences when these patients are in their forties or fifties, and that the pathological process progresses gradually, taking 20 to 30 years for clinical manifestation of dementia.