A Human-Based Integrated Framework for Alzheimer's Disease Research

Animal models of Alzheimer's disease (AD) have been extensively utilized for decades in an effort to elucidate the pathophysiological mechanisms of this disease and to test novel therapeutic approaches. However, research success has not effectively translated into therapeutic success for human patients. This translational failure is partially due to the overuse of animal models that cannot accurately recapitulate human AD etiopathogenesis or drug responses and the inadequate use of human-relevant research methods. Here, we propose how to mitigate this translational barrier by employing human-based methods to elucidate disease processes occurring at multiple levels of complexity, accounting for gene and protein expression and the impact of disease at the cellular, tissue/organ, individual, and population levels. In particular, novel human-based cellular and computational models, together with epidemiological and clinical studies, represent the ideal tools to facilitate human-relevant data acquisition, in the effort to better elucidate AD pathogenesis in a human-based setting and design more effective treatments and preventive strategies. Our analysis indicates that a paradigm shift toward human-based, rather than animal-based research is required in the face of the ever-increasing prevalence of AD in the 21st century.