Alzheimer’s disease (AD) and other, less prevalent dementias are complex age-related disorders that exhibit multiple etiologies. Over the past decades, animal models have provided pathomechanistic insight and evaluated countless therapeutics; however, their value is increasingly being questioned due to the long history of drug failures. In this Perspective, we dispute this criticism. First, the utility of the models is limited by their design, as neither the etiology of AD nor whether interventions should occur at a cellular or network level is fully understood. Second, we highlight unmet challenges shared between animals and humans, including impeded drug transport across the blood–brain barrier, limiting effective treatment development. Third, alternative human-derived models also suffer from the limitations mentioned above and can only act as complementary resources. Finally, age being the strongest AD risk factor should be better incorporated into the experimental design, with computational modeling expected to enhance the value of animal models.
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We thank R. Tweedale for critical reading of the manuscript. We acknowledge support by the estate of C. Jones, the state government of Queensland (Department of Science, Information Technology and Innovation), the National Health and Medical Research Council of Australia (GNT1176326) and the NHMRC-EU Joint Programme on Neurodegenerative Disease Research to J.G.
The authors declare no competing interests.
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Padmanabhan, P., Götz, J. Clinical relevance of animal models in aging-related dementia research. Nat Aging 3, 481–493 (2023). https://doi.org/10.1038/s43587-023-00402-4