Pursuit of precision medicine: Systems biology approaches in Alzheimer's disease mouse models

Abstract

Alzheimer's disease (AD) is a complex disease that is mediated by numerous factors and manifests in various forms. A systems biology approach to studying AD involves analyses of various body systems, biological scales, environmental elements, and clinical outcomes to understand the genotype to phenotype relationship that potentially drives AD development. Currently, there are many research investigations probing how modifiable and nonmodifiable factors impact AD symptom presentation. This review specifically focuses on how imaging modalities can be integrated into systems biology approaches using model mouse populations to link brain level functional and structural changes to disease onset and progression. Combining imaging and omics data promotes the classification of AD into subtypes and paves the way for precision medicine solutions to prevent and treat AD.

Keywords: Alzheimer's disease; Imaging; Precision medicine; Resilience; Systems biology.

Fig. 1.

Analyzing the Interacting Components of System Biology in the Study of Alzheimer’s Disease (A) The study of systems biology and the discovery of genotype to phenotype relationships involves the interaction of multiple levels: 1. biological systems, 2. environmental perturbations, 3. biological scales, and 4. clinical traits. (B) Because AD is a complex disease, modeling of biological networks is required to test and discover the relationship between factors and mechanisms. Combinations of single or multiple factors from each biological and environmental scale (A:1–4) should be included in models to determine the correlation between data types and resulting clinical outcomes. (B) shows a hypothetical model of how the factors from (A) could interact. Each factor can impact others with varying weights of influence indicated by the width of the arrows. (Created with BioRender.com).

Fig. 2.

Utility of animal models and systems biology approaches for precision medicine solutions (A) Using a translationally relevant and diverse model mouse population, (B) a vast amount of longitudinal imaging and omics data can and has been collected to develop predictive networks and (C) identify drivers of resilience. (D) These identified modulators can guide the classification of AD subtypes. Subtypes reflect a pattern or prevalence of the collected imaging and omics endophenotypes measures. Single or groups of mouse strains can then be classified into these subtypes based on the display of similar traits, and if available, compared to established human subtypes. Mice sorted into these subtypes can then directly enter the precision medicine discovery drug cycle. (E) We recently tested AD-BXD strains against established human AD subtypes to define human relevant subtypes from hippocampal RNAseq data. (F) Mouse subtypes that appropriately align with human subtypes will then proceed through the pipeline. In vitro models that recapitulate the cellular and molecular profiles of each subtype can be create and implemented to conduct compound screens. Measures of neurodegeneration, synapse number and type, axonal degeneration, and neuron excitability can be quantified to assess the result of each compound on the model system. (G) The efficacy of a select compound’s ability to alter disease course in mice of certain subtypes can then be assessed in vivo with cognitive phenotyping. Overall outcomes of this pipeline will enable precision medicine solutions to be identified per disease subtype and then potentially applied in clinical trials for humans or to refine the selection of mouse strains in future discovery trials. (Created with BioRender.com).