Several pathogenetic factors seem to contribute to the development of Alzheimer's disease (AD). Some data point to a role for traumatic brain injury (TBI), but this suggestion is not universally supported. Mayeux et al. have shown that TBI increases the risk of AD, but only through a synergistic relationship with apolipoprotein epsilon (Apo E) 4. We present the results of a cross-sectional and longitudinal study of the relationship between these factors, conducted in northern and southern Italy. We studied 337 consecutive patients with probable AD and 63 subjects with mild cognitive impairment (MCI). Information concerning head injuries was collected by interview of informants and review of medical records. Twenty-one patients with AD and 9 with MCI were found to have a history of TBI with loss of consciousness. AD and MCI patients with a history of TBI, compared with control groups matched for age, sex, education and degree of mental impairment, showed more marked depressive and behavioural disturbances (Global Deterioration Scale and Neuropsychiatric Inventory, p<0.05). Six- and 12-month follow up of both groups did not show significant differences in the rate of progression of cognitive changes. A high frequency of Apo E 4 was detected in the patients with TBI and cognitive impairment (40.5% in the AD and 11% in the MCI subgroups). The distribution of the epsilon 4 allele in our control group was 4%, comparable to that found in the Italian population. Distribution of the above parameters was similar in patients from northern and southern Italy. The higher frequency of TBI and Apo E 4 genotype among AD and MCI patients confirms the synergistic interaction of environmental and genetic factors in the development of dementia. Our data do not suggest that the presence of these two factors influences the clinical presentation or the course of the disease.