Many new treatments under development for Alzheimer disease (AD) will be disease-modifying rather than symptomatic. Clinical evaluation of these treatments will require primary and secondary prevention trials. We describe some of the methodologic challenges in designing primary prevention trials for AD and illustrate these with examples from the ADAPT (Alzheimer Disease Anti-Inflammatory Prevention Trial) Study and GEM (Ginkgo in Evaluation of Memory) Study. Primary prevention trials for AD present many design challenges. In most situations, secondary prevention trials provide the most feasible first step toward primary prevention.