Controversy exists regarding the apolipoprotein E (ApoE) epsilon 4 allele association with vascular dementia (VaD). The results range from increased epsilon 4 frequency, similar to that found for Alzheimer's disease (AD), to no association at all. Our objective was to clarify the relationship between ApoE epsilon 4 allele and cerebrovascular disease (CVD) in demented and cognitively impaired patients. We examined the ApoE phenotypes in a sample of 452 subjects: 219 with AD, 45 with VaD, 62 with mixed dementia (MD), 45 with mild cognitive impairment (MCI) without CVD, 27 in which vascular disease was the most probable cause of cognitive decline (vascular mild cognitive impairment, VMCI) and 54 normal controls (NC). The study of the epsilon 4 allele frequency showed significant differences between: AD group and the VaD, VMCI and NC groups; MCI group compared with VMCI and NC groups; and MD group versus the VaD and NC groups (p<0.05-0.0001). The frequency of the epsilon 4 allele in the VaD and VMCI groups did not differ significantly from NC. In contrast to other studies, we did not detect a relationship between ApoE epsilon 4 allele and clinically diagnosed VaD. Our results also show that the epsilon 4 allele is not associated with cognitive impairment of vascular origin. In addition, we have confirmed that the ApoE epsilon 4 allele occurs frequently in late-onset AD and we have found similar association in cognitively impaired individuals without clinical CVD. These findings should contribute to the assessment of dementia risk profile in the elderly.