The synaptic basis of cognitive reserve in Alzheimer's disease

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Alzheimer's disease (AD) is a life-changing and debilitating disease characterised by progressive neuronal cell loss and thus, cognitive decline. Interestingly, however, some individuals are protected against AD-associated brain protein pathology (AB and Tau). These patients present (post-mortem) with high-pathological protein burden in their brains, without the associated memory loss and cognitive decline. This suggests these individuals possess cognitive resilience (CR) against AD-associated brain changes. This PhD project aims to understand and characterise the synaptic and molecular basis of cognitive resilience/reserve in these individuals (CR individuals), with the aim to understand how dendritic spine and brain plasticity effects neurodegeneration.During the project I will use dendritic spine number and morphology to investigate synaptic integrity in three patient groups; patients with cognitive resilience (CR), AD-diagnosed cases and healthy (non-neurodegenerative) controls, allowing me to identify novel molecular markers of CR. The project will use transcriptomic, in -vitro and -vivo experiments in post-mortem Human brain and rat brain tissue. The project will have three aims, as follows:1. To establish brain dendritic spine/plasticity-related protein targets and investigate their localisation in post-mortem human and rat brain tissue. 2. To establish human transcriptomic profiles from cognitively resilient (CR), Alzheimer's disease (AD) and wild-type (Wt) non-neurodegenerative patient samples. 3. To establish animal models for AD, CR and Wt, and then to investigate synaptic compensation in vivo. In these models we will then use pre-identified (aims 1 and 2) protein and transcriptomic targets to establish/confirm their relationship to cognitive resilience.Ultimately, we hope to characterize particular targets (biomarkers) for cognitive resilience that may protect individuals from AD-pathology, with a long term goal of providing precision-medicine based healthcare to neurodegenerative diagnosis and treatment.