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

Document Type

Article

Publication Date

2-6-2019

Keywords

JMG

JAX Source

Neuron 2019 Feb 6; 101(3):399-411.e5.

Volume

101

Issue

3

First Page

399

Last Page

411

ISSN

1097-4199

PMID

30595332

DOI

https://doi.org/10.1016/j.neuron.2018.11.040

Grant

BrightFocus Foundation, AG057914,AG054180,AG050357,AG059778

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.

Comments

The authors thank Dr. Lynda Wilmott and Thomas Shapaker for collection of behavioral data and Kwangbom Choi, Matthew de Both, Ryan Richholt, and Ashley Siniard for assistance with RNA sequencing. The authors would also like to thank Dr. Rob Williams for thoughtful input on the project design and Drs. Vivek Philip and Ji-Gang Zhang for assistance with data analysis.

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