Deposition of amyloid beta-protein (A beta) in the brain plays a key role in the pathogenesis of Alzheimer's disease. Apolipoprotein E epsilon 4 allele (apo E-epsilon 4) is a strong risk factor for Alzheimer's disease, and there is in vitro evidence that apo E is directly involved in A beta deposition. Head injury is an epidemiological risk factor for Alzheimer's disease and deposition of A beta occurs in approximately one-third of individuals dying after a severe head injury. We report here that the frequency of apo E-epsilon 4 in those individuals with A beta deposition following head injury (0.52) is higher than in most studies of Alzheimer's disease, while in those head-injured individuals without A beta deposition the apo E-epsilon 4 frequency (0.16) is similar to controls without Alzheimer's disease (P < 0.00001). This finding provides further evidence linking apo E-epsilon 4 with A beta deposition in vivo and suggests that known environmental and genetic risk factors for Alzheimer's disease may act additively. In addition our finding indicates a genetic susceptibility to the effects of a head injury.