Despite over one hundred years of intense effort studying Alzheimer's disease (AD), we still do not understand its cause(s) and this adversely affects our ability to develop strongly effective treatments and means to prevent it. This is because our research efforts are not aligned to decipher this age-related disorder that, well after its discovery, has become a major cause of death throughout the world. We are therefore recommending a process to analyze some of the principal factors that hinder our progress in this field of research. Recognizing these barriers — and acting on such a recognition by seeking to resolve them experimentally and garnering societal support to do so — will constitute critical steps towards establishing strategies that will lead to a sorely needed paradigm shift in AD research, and ultimately to the prevention and the effective treatment of this devastating condition. This will probably also spur progress in many related neuropsychiatric disorders, and in that sense act as a seminal endeavor with far-reaching consequences. In order to accomplish this complex task, the biomedical community must acknowledge and come to a consensus about the factors that limit our progress, and then work together to generate new algorithms to tackle these fundamental issues rationally, effectively and deliberately.