To address this question we use transgenic mice carrying familial AD mutations which mimic the pathological and behavioural hallmarks of the disease.  Using this mouse model we probe whether there are tractable memory deficits during the early stages of disease pathogenesis using quantitative hippocampus dependent behavioural assays. We further combine these quantitative behavioural assays with viral tracings to define anatomically distinct LC neural pathways projecting to hippocampus that can be causal in modulating memory and behaviour. Differential susceptibility of LC neurons during early stages of disease pathogenesis will be further studied both in vivo and in vitro using primary LC neuronal cultures. Using chemogenetics we will finally manipulate these differentially vulnerable LC neurons to assess their causal role in driving early behavioural deficits. The combination of these approaches enables us to delineate how neural circuit alterations influence behaviour during early AD.