The Aged Dog as a Natural Model of Alzheimer’s Disease Progression

Abstract

Alzheimer’s disease is the most common cause of dementia in humans and is rapidly becoming an unmet medical need of epidemic proportions. Although billions of dollars have been allocated to this cause, more than 190 putative Alzheimer’s disease drugs have failed in the clinic, exemplifying the high risk-to-reward ratio of therapeutic development. One factor implicated in this high failure rate is the limitation of animal models to accurately predict clinical outcomes. The fact that some of these models, such as transgenic mice, have a 100% failure rate for predicting clinical outcomes of putative drugs exemplifies their limitations and the need for additional models that better recapitulate the multifactorial nature of Alzheimer’s disease progression. Aged dogs naturally develop Alzheimer’s-like neuropathological changes, as well as cognitive-domain specific impairments consistent with early stages of Alzheimer’s disease progression. Moreover, cross-sectional data in differentially aged dogs suggests that Alzheimer’s relevant biomarker changes are also found in dogs and could be used to monitor early stage Alzheimer’s-like disease progression. The aged dog model accurately predicted the clinical outcome of both the gold standard symptomatic Alzheimer’s disease therapeutic, donepezil, and the failure of active fibrillary amyloid vaccination strategies. The aged dog, therefore, provides a valuable preclinical animal model for assessing Alzheimer’s disease therapeutics with demonstrable translational value for predicting clinical outcomes. Given the translational validity of the model, it is likely that Alzheimer’s disease clinical research could also be used for improving care of senior dogs.