Incorporating genetic diversity into a mouse model of Alzheimer's disease resulted in greater overlap with the genetic, molecular, and clinical features of this pervasive human disease, according to a study published in Neuron earlier this week. The study also suggests that adding genetic diversity may be key to improving the predictive power of studies using mouse models and increasing their usability for precision medicine research for Alzheimer's.
"This is the first study to show that you can replicate many of the molecular features of Alzheimer's disease in a genetically diverse mouse model," said National Institute of Aging (NIA) director Richard J. Hodes, M.D. "It points to a strategy for better use of mouse models for precision medicine research—both basic and translational—for Alzheimer's disease."
In this study, the researchers, led by Catherine C. Kaczorowski, Ph.D., an associate professor at the Jackson Laboratory, tested the idea that including more real-world genetic variation into a mouse model of Alzheimer's would improve the translatability of the model. To do this, they combined a well-established mouse model of familial Alzheimer's (5XFAD) with a genetically diverse set of mice. All members of this family of transgenic mice therefore carry the high-risk human familial Alzheimer's genes but otherwise have very different genetic make-up. The detailed analysis of this new panel of mice (referred collectively as AD-BXD), showed a high degree of overlap with the genetic, molecular, pathologic, and cognitive features of Alzheimer's. Moreover, in the presence of identical Alzheimer's risk genes, the differences in genetic background led to profound differences in the onset and severity of the pathologic and cognitive symptoms of Alzheimer's.
Through a series of comparative analyses, the research team also discovered that one mouse strain, C57BL/6J, commonly used to generate Alzheimer's transgenic mouse models, harbors resilience factors that lessen the impact of Alzheimer's risk factor genes. This new finding has two important implications. First, it suggests that Alzheimer's mouse models with this genetic background may not be suitable for testing of novel therapeutic agents and may explain the poor predictive power of drug screening studies using the current Alzheimer's transgenic mouse models. Second, by using the AD-BXD panel, the protective genes from the C57BL/6J strain and their mechanisms can be precisely identified leading to new candidate targets for Alzheimer's prevention.
The authors noted that the AD-BXD panel represents a new tool for better understanding the heterogeneous nature of normal aging and Alzheimer's, and for precisely identifying molecular factors that lead to resilience to genetic and environmental disease risk factors.