Alzheimer’s disease (AD) is a complex disease for which no broadly successful treatment exists. Despite enormous investment and even with a controversial recent drug approval, nothing has convincingly slowed the progression of Alzheimer’s disease. The first clinical signs of AD dementia present many years after the disease has begun its course. The disease is characterized in the brain by the presence of amyloid plaques and neurofibrillary tangles that associate with inflammation and synaptic loss, yet treatments targeting brain pathology, such as amyloid beta plaques—thought to be responsible for the initiation of the progression of AD—have been failures. The challenge is very similar to the adage that we are trying to describe an elephant by exploring it in a dark room. We need to bring light into the system. More validated, interconnected models of AD are needed. We propose to generate or capture and integrate genetics and gene expression signatures that represent the key aspects of AD initiation and progression. A pathogenesis network map of Alzheimer’s disease, relating the key signatures of AD, is proposed. Each mapped signature will result in predicted drugs targeting that aspect of AD. The signatures will be connected in a systems biology framework that will allow, for the first time, molecular aspects of the disease to be integrated with each other. We will test and validate predicted drugs and regulatory programs for the signatures we discover to provide a set of validated, translated signatures of AD.