A strong association has been described in cross-sectional studies between the epsilon 4 allele of the apolipoprotein E and late-onset Alzheimer's disease (LOAD). This study addresses the relationship between disease progression and the epsilon 4 allele in 62 sporadic LOAD (onset at age 70 and over) patients. Disease progression was estimated retrospectively with the Mini-Mental State Examination (MMSE) amounting to 4.7, 3.8, and 2.2 points per year (sex-adjusted test for trend: p = 0.01) and with the Clinical Dementia Rating (CDR) to 0.76, 0.67, and 0.42 units per year (p = 0.03) in -/-, epsilon 4/-, and epsilon 4/epsilon 4 patients. The proportion of patients with fast progression decreased (p < or = 0.005) and with slow progression increased (p = 0.002) with increasing epsilon 4 gene dose. These findings were confirmed in a smaller sample of 28 patients for whom longitudinal assessments of MMSE were available and when nonlinear progression of the disease was accounted for in a stratified analysis. These data suggest that disease duration might be longer in epsilon 4 carriers and that this might at least partly account for the cross-sectional association between the epsilon 4 allele and LOAD.