Producing a valid animal model of apolipoprotein E (APOE )-based dementia is critical to understanding the etiology and progression of late-onset Alzheimer's disease (AD). Unfortunately, no such model exists. Herein, I review all past and present attempts to create an APOE-based model with suggestions on how to reproduce AD in a mouse. Our ability to succeed in recreating late-onset AD will depend on the identification of new genetic markers in addition to the validation of nongenetic factors thought to increase the risk of dementia. These new factors can then be incorporated into an APOE-expressing animal for mechanistic studies and identification of new drug targets. © 2011 Springer Science+Business Media, LLC.