In this study the authors assessed the effects of various levels of APOE2 expression, routes of delivery, and the extent of pre-existing amyloid pathology on AAV-APOE2-mediated alteration of amyloid pathology using a widely used mouse model of brain amyloidosis (PDAPP mice) as well as a mouse model that develops APOE4-dependent amyloid deposition (APP.PS1/TRE4 mice). This study shows that direct intracerebral gene delivery of APOE2 via an AAV vector significantly reduces brain Abeta and amyloid deposition in these transgenic mouse models of AD and rescues the detrimental effects of both APOE4 as well as murine Apoe on brain amyloid pathology.  The data also demonstrate that the “efficacy” of AAV-APOE2 gene delivery to decrease amyloid pathology in these mouse models strongly depends on the level of APOE2 expression and pre-existing amyloid pathology at the time of vector administration, rather than the cellular source of APOE2 or the route of administration. In addition, the results show that intrathalamic delivery of APOE2 using an AAV vector results in widespread brain distribution of APOE2 and a broad reduction of brain Abeta burden following a single injection in APP.PS1/TRE4 mice. In conclusion this study provides direct evidence for a qualitative “protective” effect of APOE2 on brain amyloid burden and shows that raising (rather than reducing) brain APOE2 to a sufficient level effectively reduces amyloid pathology in mice where the latter is primarily due to APOE4 expression. Thus, gene delivery of APOE2 may represent a promising therapeutic strategy especially if used early in the course of the disease.