The results of randomized controlled trials of nutritional interventions aimed at preventing cognitive decline or dementia in older people have been largely disappointing. A reasonable argument can be made that this is at least in part because the design of primary prevention trials in older people is not straightforward and that the complexities of such trials are not readily apparent and commonly remain not fully recognized. This article analyzes some of the difficulties associated with identifying and enrolling study participants in long-term prevention trials, with available data from three large, recently published trials used as examples. This analysis also serves to identify examples of good practice and areas for further research. Randomized controlled trials remain the single most important tool in the epidemiological arsenal for identifying the effects of specific interventions, but consideration of critically important design features is essential.