02465nas a2200289   4500000000100000008004100001260001500042653002400057653001700081653002100098653001900119653002200138653002700160100003500187700002600222700002500248700002200273700003200295700002200327700002100349245014400370856007200514300001100586490000800597520155600605022001402161       2019                            d  c2019-09-1510aAlzheimer's disease10aanimal model10aDrug development10aefficacy model10aExternal validity10atranslational research1 aDésirée H. Veening-Griffioen1 aGuilherme S. Ferreira1 aPeter J. K. Van Meer1 aWouter P. C. Boon1 aChristine C. Gispen-de Wied1 aEllen H. M. Moors1 aHuub Schellekens00aAre some animal models more equal than others? A case study on the translational value of animal models of efficacy for Alzheimer's disease  uhttps://www.sciencedirect.com/science/article/pii/S0014299919304765  a1725240 v8593 aClinical trial failures (>99%) in Alzheimer's disease are in stark contrast to positive efficacy data in animals. We evaluated the correlation between animal and clinical efficacy outcomes (cognition) in Alzheimer's disease using data from registered drugs as well as interventions tested in phase II or III clinical trials for Alzheimer's disease. We identified 20 interventions, which were tested in 208 animal studies in 63 different animal models. Clinical outcome was correlated with animal results in 58% of cases. But, individual animal models showed divergent results across interventions, individual interventions showed divergent results across animal models, and animal model outcomes were determined with 16 different methods. This result is unsurprising due to poor external validity (what do we model) of the animal models. Although the animal models all share Alzheimer's disease symptoms, none represents the whole syndrome. Investigators did not motivate why one model was chosen over another, and did not consider the ways the disease phenomena were generated (spontaneous, (experimentally) induced or by genetic modification), or the species characteristics, which determine the outcomes. The explanation for the lack of correlation between animal and human outcomes can be manifold: the pathogenesis of Alzheimer's disease is not reflected in the animal model or the outcomes are not comparable. Our conclusion is that currently no animal models exist which are predictive for the efficacy of interventions for Alzheimer's disease.  a0014-2999