The ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD) compared to the more common ε3 allele. Studies in animal models and humans suggest that apoE4 exhibits both loss-of-function and gain-of-toxic-function compared to apoE3. In regulating amyloid pathology, apoE4 is less efficient than apoE3 in mediating the clearance of amyloid-β (Aβ) peptides and is more dominant in promoting Aβ aggregation. Outside the Aβ pathway, apoE4 is also less efficient in transporting lipid and supporting synapses. To answer the important yet unanswered question whether it is better to increase or decrease apoE levels in AD therapy, we have developed new animal models that allow for inducible and cell-type specific expression of apE3 and apoE4.