There has been considerable progress in the prevention and treatment of cardiovascular disease, reducing the population burden of cardiovascular morbidity and mortality. Recently, some randomized trials, including the SPRINT (Systolic Blood Pressure Intervention Trial), have suggested that improvements in cardiovascular risk factors may also slow cognitive decline and reduce the eventual development of dementia. Unfortunately, the randomized trial template that has been used repeatedly to successfully demonstrate reductions in major adverse cardiac events faces several design and analytic obstacles when applied in the context of cognitive decline and dementia. Here, we review these obstacles, motivated by SPRINT and the context of selecting an appropriate cognitive end point for future preventive randomized trials. A few options are available, spanning neuropsychological test scores or composites reflecting specific domains of cognitive function, adjudicated cognitive impairment, or potentially physiological biomarkers. This choice entails considerations around statistical power, modes of ascertainment, the clinical relevance of treatment effects, a myriad of statistical issues (interval censoring, missing data, the competing risk of death, practice effects, etc), as well as ethical considerations around equipoise. Collectively, these considerations indicate that trials aiming to mitigate the cardiovascular contribution to cognitive decline and dementia will generally need to be large, inclusive of a wide age range of older adults, and with multiple years of follow-up.