Systems Genetic Analysis of Cognitive Resilience Using Multi-Parent Crosses

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PROJECT SUMMARY/ABSTRACT Cognitive resilience is a phenomenon whereby individuals are resistant to the most damaging effects of aging on cognition – individuals that maintain normal cognitive function despite being long-lived (e.g. centenarians) are said to exhibit high cognitive reserve or resilience depending on the conceptual definitions (see Reserve and Resilience NIA Consortium). Genetic factors promoting cognitive reserve and resilience may thus provide key targets for treatment and prevention of cognitive decline across a spectrum of age-related dementias including Alzheimer’s disease (AD) and Alzheimer’s disease related dementias (ADRD). Our overall objective is to identify drivers of cognitive reserve and resilience by using network approaches to integrate data collected from Diversity Outbred (DO) mouse models with human data. Data generated as part of the parent award indicates that regional changes in cell-type composition may be a significant contributing factor in determining individual differences in cognitive reserve and resilience. Recent advances in brain-wide spatial analyses of correlates of brain reserve and resilience, and particularly the advent of high throughput platforms for large-scale immunohistochemistry (IHC) to label multiple cell types throughout hundreds of mouse brains, now make it feasible to assess region and cell type specific hallmarks of cognitive reserve and resilience and clinically relevant traits in the same mice as used for assessing cognition, motor, sleep, and metabolic symptoms, representing a powerful complement to our ongoing work and adding a new layer of information regarding regional and cell-type specificity to our multi-scale network model. With the proposed supplement, we will be able to identify changes in specific brain regions and cell types associated with cognitive reserve and their relationship to transition towards Alzheimer’s disease and age-related dementias. This project will deliver novel brain regions and cell types for promoting healthy brain aging (reserve) and resilience to aging. We will annotate, curate, and rapidly disseminate the data to the broad scientific community prior to publication to maximize the usability of these data for meta-analysis and systems biology research.