To provide better prevention and treatment, we need to understand the environmental and genetic risks of Alzheimer’s disease (AD). However, the definition of AD has been confused with dementia in many studies. Thus, the overinterpretation of genetic results with respect to drug mechanisms and targets may partly explain the controversies in the field. Here, we analyze the different forms of genetic risk of AD and how these can be used to model the disease. We emphasize the importance of studying gene variants in the right cell types and in the right pathological context. The lack of mechanistic understanding of genetic variation has become the main bottleneck in the search for new drug targets for AD.