Identifying genetic factors that increase cognitive reserve: A theoretical approach

Abstract

Studies have demonstrated that some individuals display pathological hallmarks of Alzheimer's disease (AD) but are not afflicted with cognitive decline. The ability to maintain cognitive function despite the presence of pathology is referred to as cognitive reserve. This project aims to identify the molecular pathways involved in cognitive reserve using Drosophila melanogaster (Drosophila) models of AD. Specifically, a theoretical approach using experimental evolution to drive a population of AD-like Drosophila carrying a tau mutation to develop cognitive reserve is proposed. To accomplish this, a population of AD-like Drosophila will be placed in a single population cage along with wild-type flies and forced to compete for food and water. The first generation of AD-like Drosophila will be generated using random mutagenesis of the initially isogenic AD-like fly. The selected tau mutant displays a rough eye condition which allows for easy distinction between tau mutant and wild-type flies. It is hypothesised that AD-like flies with cognitive decline will be unable to survive because their limited cognitive abilities will prevent them from effectively competing for food and water. In contrast, AD-like flies with mutations that promote cognitive reserve will be better capable of survival. After 90-99% of mutant flies have died, the surviving mutant flies will be back-crossed to the P1 mutant to maintain tau mutation stability. It is expected that artificial selection will result in the creation of a generation of tau mutant flies that demonstrate cognitive abilities comparable to those of wild-type flies despite maintaining an AD-like tau mutation. This approach will monitor the successful trajectory of the evolution of increased cognitive reserve through survival curve analysis and measures of cognition. A limitation of the method is that only a dominant mutation or series of dominant mutations would be identified using this approach.

Keywords

• Alzheimer's disease
• tauopathy
• experimental evolu