Apolipoprotein E (APOE), the most important genetic predisposition factor for Alzheimer’s disease, long has been known for its effect on the formation of amyloid plaques, and more recently for its importance in glial cell activation. There is evidence for another role of APOE on neuron function independent of amyloid plaques. Since some neurons are more vulnerable than others to neurodegeneration, we ask in this proposal whether APOE also could modulate their vulnerability. Our aim is to both better understand the role of APOE in AD, as well as the vulnerability of specific neurons. The most vulnerable neurons of the brain are the ones from the layer II of the entorhinal cortex (ECII), which are crucial for new memory formation. Their early degeneration hinders the ability to form new memories at the onset of the disease. We previously compared the full inventory of all proteins present in these ECII neurons in mice with different alleles of human APOE: the risk allele, the neutral one and the protective one. Preliminary experiments now indicate that 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 want to pinpoint more precisely the molecular events that occur in vulnerable neurons in the presence of the risk allele of APOE to understand how these events could lead to the death of the neurons. Proteins that make ECII neurons more vulnerable, and that are modulated by APOE, could represent new drug targets to prevent ECII neurons from degenerating, and thereby halt the progression of the disease.