Considering the emerging literature indicating that the detrimental properties of apoE4 may be related to N- and C-terminal domain interaction, and/or the generation of a C-terminal truncated apoE fragment, the use of small molecules that disrupt apoE4 domain interaction or inhibit the neuron-specific apoE proteolysis may be viable therapeutic options for Alzheimer’s disease treatment. This evidence concerns the gene APOE and early-onset autosomal dominant Alzheimer disease.