APOE, the most important genetic predisposition factor for sporadic Alzheimer’s disease, long has been known for its effect on the formation of amyloid plaques. There is evidence for another role of APOE on neuron function independent of amyloid beta. We have developed tools to make the full inventory of all proteins present in a specific type of neuron, in particular in neurons that display differential vulnerability to neurodegeneration. Entorhinal cortex layer II (ECII) and hippocampal CA1 neurons are both crucial for new memory formation, and are the most susceptible to degeneration. This proposal will comprehensively profile ECII and CA1 neurons in mice bred to carry the different human alleles of APOE, and investigate whether the human risk allele of APOE is putting ECII neurons in an increased vulnerability state compared with the neutral or the protective alleles of APOE. We also have evidence that ECII neurons could display different profiles in males and females, because they are equipped with sensors for estrogen. In light of the increased prevalence of AD for women, we will investigate if APOE and sex interact to alter the vulnerability of ECII neurons. Potential proteins modulated by APOE and/or sex that make ECII neurons more vulnerable could represent new drug targets to prevent ECII neurons from degenerating.