ABCA1 promotes cholesterol efflux from cells and is required for maintaining plasma cholesterol levels. Cholesterol homeostasis is important in the production of β-amyloid (Aβ), a peptide that is overproduced in Alzheimer's disease (AD). Overexpression of ABCA1 can be achieved by stimulating Liver X Receptors (LXR), and changes in Aβ have been reported after LXR stimulation in vitro. To determine whether ABCA1 could alter endogenous Aβ levels, we used two different in vivo systems. We first examined the effects of an LXR agonist (TO-901317) on wild-type mice and found an increase in brain ABCA1 and apoE levels, which caused an increase in plasma cholesterol. This was accompanied by a decrease in brain Aβ levels. We then examined endogenous Aβ levels in ABCA1 knockout mice and found that, despite having no ABCA1, lowered brain apoE levels, and lowered plasma cholesterol, there was no change in Aβ levels. To assess these in vivo models in an in vitro system, we designed a model in which cholesterol transport via ABCA1 (or related transporters) was prevented. Switching off cholesterol efflux, even in the presence of TO-901317, caused no change in Aβ levels. However, when efflux capability was restored, TO-901317 reduced Aβ levels. These data show that promoting cholesterol efflux is a viable target for Aβ reducing strategies; however, knockout of cholesterol transporters is not sufficient to alter Aβin vitro or in vivo.