A few years ago at the European Alzheimer's Disease Consortium-Alzheimer's Disease Cooperative Study meeting in Geneva we discussed with Leon Thal the possibility of building large multi-domain primary preventive international trials for Alzheimer's disease (AD) both in North America and in the European Union. AD is a multifactorial phenomenon, and we will be more likely to succeed in preventive trials if we build a strategy using all potential protective factors to have the most potential effect instead of a simple and unique intervention. Leon Thal suggested that this could have a much bigger impact than all the drugs we might ever hope to develop. The main objective of this article is to present the rationale for multi-domain preventive approaches.