OBJECTIVE: Given the strong association of the apolipoprotein E (apoE) allele epsilon 4 with late-onset Alzheimer dementia or multi-infarct dementia, we tested whether normal older adult men with at least one epsilon 4 allele demonstrate subclinical changes in cognition and perform more poorly on tests of cognitive function compared with subjects without the epsilon 4 allele. DESIGN: Matched-pair design of normal adult male (average age, 63 years) fraternal twins. SETTING: Subjects voluntarily participated on an outpatient basis at a research or medical center facility. PARTICIPANTS: Members of the National Heart, Lung, and Blood Institute twin panel third examination previously genotyped for apoE. MAIN OUTCOME MEASURE: Education-adjusted scores on several neuropsychological tests were compared in twins discordant for the apoE epsilon 4 allele. Subjects with documented cerebrovascular disease were excluded. RESULTS: Among 20 fraternal twin pairs discordant for the presence of epsilon 4, twins with the epsilon 4 allele demonstrated poorer mean performance than their co-twins without the epsilon 4 allele. This relationship was also noted cross-sectionally where age- and education-adjusted scores of 50 individual twin subjects with at least one epsilon 4 allele demonstrated poorer performance compared with 138 individual twins without an epsilon 4 allele. CONCLUSIONS: The apoE epsilon 4 allele may be associated with decreased cognitive function in discordant twin pairs. Our results suggest that epsilon 4 may represent a potential marker for accelerated cognitive aging and such individuals may be at greater risk for development of late-onset Alzheimer dementia or multi-infarct dementia.