System Genetics to Identify Modifiers of Alzheimer’s Disease
The age of onset and severity of Alzheimer’s disease (AD) is subject to extreme variation across the human population. Despite millions of dollars and decades of research, over 70 percent of this variation remains unexplained. This proposal seeks to identify genes that modify the onset and severity of AD in a well-characterized, genetically diverse mouse population. Subsequent gene therapy will be used to validate identified genes and rescue/treat memory failure in a mouse model of AD. Results of this research will make a significant contribution to the understanding of the genetics of AD and have the immense potential to translate into individualized therapies for aging humans.
Note: This grant was originally awarded to the The University of Tennessee Health Science Center in Memphis, Tennessee and transferred to The Jackson Laboratory in Bar Harbor, Maine on October 3, 2016.
The main goal of our project is to identify new genes that may modify the age at which a person will develop symptoms of Alzheimer's disease (AD), termed “age-at-onset.” Another goal is to establish how these modifier genes influence brain cell networks necessary for proper memory function, which may point to new therapeutic targets to delay or even prevent AD’s onset.
The identification of modifier genes in humans has been difficult due to differences in environment and lifestyle factors. In order to circumvent some of the barriers to gene identification in human AD, we will create a panel of genetically diverse mice harboring causal familial AD mutations and measure cognitive abilities, the functional connectivity between key memory regions of the brain, and AD-specific brain pathology across the lifespan. Based on our analysis of a small set of AD strains, we have already identified a few genes that may modify the onset and severity of AD. To directly test if and how modifier genes might modulate the age-at-onset and severity of AD, we will manipulate their expression in key memory regions using sophisticated tools and measure resulting changes in cognitive abilities, functional connectivity between key memory regions of the brain, and AD-specific brain pathology as a function of age.
The success rate of treatments for AD, based on evidence from animal studies, is dreadful (an approximate 99 percent failure rate). Clearly there are major roadblocks standing in the way of our ability to translate basic scientific discoveries to improve human health. Two major reasons proposed for the high failure rate of AD drugs include: 1) a narrow understanding of the genetic complexity of human AD, and 2) reliance on genetically engineered mouse models (GEMMs) created on one or a few inbred backgrounds that don’t reflect genetic diversity of mouse, let alone human, populations. Together, these limitations have hindered development of models representative of the human disease. Our biomedical research community desperately needs the next generation of murine resources to better model genetically admixed human populations and human disease, a major priority area identified by the National Institute on Aging (NIA) and National Institutes of Health (NIH). A major innovation here is that we will introduce and exploit genetic variation in a mouse model of AD to identify new genetic factors and mechanisms involved in the onset and progression of AD symptoms, and test their relevance in human disease.
Identification of modifier genes and their downstream targets, which has proven challenging in human studies, is a critical step toward the development of both mechanistic-based treatments and personalized therapeutics that would maintain cognitive function in humans. The identification of genetic variants and/or downstream changes in hippocampal and prefrontal cortex functional connectivity also has the tremendous potential to provide biomarkers for earlier detection and more effective treatment in humans.
About the Researcher
As a predoctoral recipient of a Ruth L. Kirschstein National Research Service Award from NIH (mentors: John Disterhoft, Northwestern University, and Nelson Spruston, Janelia Farms), I laid the groundwork for the proposed research using various behavioral assays to characterize the onset of cognitive decline in mouse models of aging and Alzheimer’s disease (AD). These initial studies drove me to develop new tools and strategies to identify causal mechanisms underlying changes in neuronal and memory phenotypes. To this end, under the NIH K99/R00 grant mechanism, I successfully developed and validated a novel proteomics strategy to monitor and quantitate plasma membrane ion channels and receptors, resulting in the discovery of new drug targets for cognitive enhancement. These discoveries have led to a new challenge of deciphering which drug targets and interventional strategies will directly benefit humans, as the low predictive power of preclinical studies is a major roadblock in the translation of basic scientific discoveries to improved human health. Since establishing my own lab at the University of Tennessee Health Science Center in 2013, I have been working to develop more efficient, predictive, and powerful mouse models for bridging the preclinical to clinical gap, one that has been plagued by a record of poor reproducibility and translatability of efficacy studies using current AD models. If successful, the approaches and tools we are now developing will enable rapid mouse-to-human translational validation on a scale that far surpasses what has been reasonably achievable using standard AD models. Using multi-scale mouse and human datasets, and validation studies in murine models, we now have proof that our innovative models will identify novel genetic factors and mechanisms that are highly relevant to cognitive aging and AD.
When I was in graduate school, there was a great deal of research focused on enhancing longevity (lifespan). The consequences of extending lifespan at a rate that exceeded our ability to maintain cognitive health was a major concern of mine. My concern for our elderly, and their quality of life, led me to focus my research program on identifying causative events that underlie cognitive decline in “normal” aging and Alzheimer’s disease.
The generosity of the BrightFocus donors is especially important because it will enable my research program to expand into an entirely new, but critically important, area. This new research direction is focused on understanding the complex genetic and environmental factors that underlie Alzheimer’s-related neural network dysfunction and memory failure.
O'Connell KMS, Ouellette AR, Neuner SM, Dunn AR, Kaczorowski CC. Genetic background modifies CNS-mediated sensorimotor decline in the AD-BXD mouse model of genetic diversity in Alzheimer's disease. Genes Brain Behav. 2019 Aug 5:e12603. doi: 10.1111/gbb.12603. [Epub ahead of print] PubMed PMID: 31381246.
Neuner SM, Heuer SE, Huentelman MJ, O'Connell KMS, Kaczorowski CC. Harnessing Genetic Complexity to Enhance Translatability of Alzheimer's Disease Mouse Models: A Path toward Precision Medicine. Neuron. 2018 Dec 21. pii: S0896-6273(18)31049-3. doi: 10.1016/j.neuron.2018.11.040. [Epub ahead of print] PubMed PMID: 30595332.
First published on: July 21, 2016
Last modified on: June 30, 2020