Pathological synergism between amyloid-beta and apolipoprotein E4--the most prevalent yet understudied genetic risk factor for Alzheimer's disease.

This review focuses on apolipoprotein E4 (apoE4), the most prevalent genetic risk factor of Alzheimer's disease, and on in vivo and in vitro model studies of the mechanisms underlying its pathological phenotype. The review will first center on in vivo studies with transgenic mice that express human apoE4 and other human apoE alleles, and on the extent to which this model mimics and reproduces the human apoE4 phenotypes. The second part of this review will address apoE4-related in vitro studies, with particular emphasis on the effects of the state of lipidation of apoE4 on its biochemical properties and on the extent to which the in vitro results can be generalized and applied to the in vivo situation. The third part of this review will focus on a novel pharmacological in vivo system that was recently developed in our laboratory, which is based on activation of the amyloid cascade in apoE transgenic mice by prolonged inhibition of the Abeta-degrading enzyme neprilysin and on what this system and its high spatio-temporal resolution has taught us about the mechanisms underlying the pathological effects of apoE4 in vivo.