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Neuron. 2019 Feb 6;101(3):399-411.e5. doi: 10.1016/j.neuron.2018.11.040. Epub 2018 Dec 27.

Harnessing Genetic Complexity to Enhance Translatability of Alzheimer's Disease Mouse Models: A Path toward Precision Medicine.

Author information

1
The Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA; The Jackson Laboratory, Bar Harbor, ME 04609, USA.
2
The Jackson Laboratory, Bar Harbor, ME 04609, USA; Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA.
3
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
4
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
5
The Jackson Laboratory, Bar Harbor, ME 04609, USA. Electronic address: catherine.kaczorowski@jax.org.

Abstract

An individual's genetic makeup plays a large role in determining susceptibility to Alzheimer's disease (AD) but has largely been ignored in preclinical studies. To test the hypothesis that incorporating genetic diversity into mouse models of AD would improve translational potential, we combined a well-established mouse model of AD with a genetically diverse reference panel to generate mice that harbor identical high-risk human mutations but differ across the remainder of their genome. We first show that genetic variation profoundly modifies the impact of human AD mutations on both cognitive and pathological phenotypes. We then validate this complex AD model by demonstrating high degrees of genetic, transcriptomic, and phenotypic overlap with human AD. Overall, work here both introduces a novel AD mouse population as an innovative and reproducible resource for the study of mechanisms underlying AD and provides evidence that preclinical models incorporating genetic diversity may better translate to human disease.

KEYWORDS:

5XFAD; Alzheimer’s; BXD; amyloid; genetic diversity; genetic risk score; mouse models; resilience; susceptibility; translational

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