Recent work provided evidence that the apolipoprotein (apo) E polymorphism is associated with late-onset sporadic Alzheimer's disease. The major histological hallmarks of Alzheimer's disease are the extraneuronal deposition of A4/beta-amyloid and the intraneuronal formation of neurofibrillary tangles, the latter correlating strongly with the psychometric status. We examined the relationship between the apo E polymorphism and Alzheimer's disease-related histological changes using a staging system which accounts for the progression of the disease over time and correlates well with the cognitive decline ante mortem. We observed a significant positive correlation between both neurofibrillary changes and A4/beta-amyloid deposits and the epsilon 4 gene dose. We estimated that the presence of one apo E4 allele leads to an earlier onset of the histopathological process of about one decade. The association of both types of Alzheimer's disease-related changes with the prevalence of the epsilon 4-allele suggests that the apo E polymorphism causally contributes to the development of Alzheimer's disease.