Alzheimer’s disease, based on the genetics of the disease and the closely related frontotemporal dementia, replicate at least some of the pathology. Researchers have been successful at modeling very specific aspects of Alzheimer’s disease in the mouse (e.g., plaques, tangles). Although these are incomplete models of the human disease, they have been well received in the field as potentially relevant models for use in drug discovery.
Patients with Alzheimer’s disease will display both amyloidopathy and tauopathy; however, scientists often focus, in a reductionist way, on one or the other in an animal model. A participant added that even though the anatomy in the mouse is different than the human, mutant tau mice are relatively good models in that they recapitulate tau-dependent neurodegeneration. This has led a number of companies to focus on antibodies that block tau-dependent neurodegeneration in these mouse models.
Hyman reiterated that mouse models are partial, or incomplete, models of the overall human phenotype. In an animal model, pathological changes are studied in the context of a unique and isolated event (i.e., lesion) over a relatively short period of time. Alzheimer’s disease, as it occurs in humans, is the sum of how lesions occur and evolve over the course of many years or decades. Mapping where in the evolution of the human disease an individual mouse phenotype model fits is an important and often uncertain piece of information. Hyman questioned the hypotheses tested in humans that do not have exact correlates in animal models (e.g., differences in when amyloid deposition occurs between animal models and in human disease).
Several participants also discussed the use of imaging and fluid biomarkers in both animal models and clinical research (e.g., positron emission tomography or PET); ligands that can identify beta-amyloid load in the brains of humans; analysis of beta-amyloid tau and phospho-tau as biomarkers in cerebrospinal fluid. These types of biomarkers are now used for early diagnosis and to monitor disease progression in humans and many participants discussed the need to translate them back into animal models. As new therapeutics are examined, using similar biomarkers in both animal models and humans may allow for better translation of animal findings into humans. It was noted that the Alzheimer’s Disease Neuroimaging Initiative (ADNI) is working toward Standardization of Alzheimer’s disease biomarkers across the 57 ADNI sites, enhancing quality assurance, quality control, and better analysis of the clinical and imaging data in the ADNI public database.