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Utility of spontaneous animal models of Alzheimer’s disease in preclinical efficacy studies

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Abstract

Spontaneous animal models of Alzheimer’s disease (AD) offer the potential to bridge the translational gulf between promising rodent studies and failed human clinical trials. In this review, the relationship between cell biology, neuropathology, clinical phenotype and biomarker progression in human AD is summarized. Genetically altered animals have provided key insights into the cell biology of AD and, together with emerging stem cell systems, remain the most effective means to disentangle the entwined mechanisms that underlie AD. Translating therapeutic success from these models of familial AD to late onset human AD has been challenging. Spontaneous models of AD do not harbor AD-associated mutations and could potentially be used to demonstrate greater generalizability of new therapies to late onset AD. The value of such models has been advanced primarily on the basis of similar amyloid (and far less frequent, tangle) neuropathology. While these models are promising, this alone is insufficient for use of these models to assess efficacy of potential therapies. The correlation between progression of neuropathology and cognitive phenotype and the association of these with biomarker progression in these models is discussed, with an emphasis on the dog and non-human primates. Currently, interventional studies using these models are hampered by use of a variety of outcomes that are not easily comparable with those used in human trials and do not permit longitudinal assessment. Additional studies aimed at closing the gap between neuropathology and usable outcome measures would support more accurate subject selection, assessment of target engagement and evaluation of therapeutic efficacy.

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    Caroline J. Zeiss

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Zeiss, C.J. Utility of spontaneous animal models of Alzheimer’s disease in preclinical efficacy studies. Cell Tissue Res 380, 273–286 (2020). https://doi.org/10.1007/s00441-020-03198-6

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