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OBJECTIVE: To determine the influence of apolipoprotein E on cognitive decline in a cohort of elderly men and women. DESIGN: Prospective study. SETTING: Scotland, Ireland, and the Netherlands. PARTICIPANTS: Five thousand eight hundred four subjects aged 70 to 82 from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). MEASUREMENTS: Subjects were assessed at baseline and over a mean 3.2-year (range 0.7–4.2) follow-up for memory (Picture-Word Recall), speed of information processing (Stroop and Letter-Digit Coding), global cognitive function (Mini-Mental State Examination), and activities of daily living. RESULTS: At baseline, subjects with apolipoprotein E4 versus those without E4 had poorer memory performance (mean score difference −0.20 (95% confidence interval (CI)=−0.31 to −0.09) for immediate recall and −0.32 (95% CI=−0.48 to −0.16) for delayed recall and slower information processing (difference in Stroop, 2.79 seconds, (95% CI=1.20–4.28); Letter-Digit score, −0.36, (95% CI=−0.77–0.05). Subjects with apolipoprotein E4 showed a greater decline in immediate (−0.22, 95% CI=−0.33 to −0.11) and delayed (−0.30, 95% CI=−0.46 to −0.15) memory scores but no significant change in speed of information processing (Stroop, P=.17; Letter-Digit, P=.06). Memory scores decreased 2.5% from baseline in those without E4, 4.3% in E4 heterozygotes ( P=.01 for immediate and P=.03 for delayed, vs no E4) and 8.9% to 13.8% in E4 homozygotes ( P=.04 for immediate and P=.004 for delayed, vs heterozygotes). Apolipoprotein E4 was associated with greater decline in instrumental activities of daily living ( P<.001). Cognitive decline was not associated with lipoprotein levels. CONCLUSION: Findings in PROSPER indicate that E4 is associated with more-rapid cognitive decline and may, therefore, predispose to dementia. [ABSTRACT FROM AUTHOR]