Nuclear receptors are ligand-activated transcription factors that act as global regulators of metabolism and inflammation. Given their broad range of actions and their salutary effects in promoting normal metabolism these receptors are attractive targets for drug development to treat a variety of CNS disorders. Alzheimer’s disease is associated with impaired clearance of soluble forms of β-amyloid (Aβ) from the brain, a process normally facilitated by Apolipoprotein E (ApoE). ApoE expression is transcriptionally induced through the coordinate action of the nuclear receptors PPARγ:RXR and LXR:RXR. Oral administration of PPARg, LXR or RXR agonists, to murine models of Alzheimer’s disease resulted in elevated levels of ApoE in the brain and the enhanced and sustained clearance of soluble Aβ. ApoE-based HDLs stimulate the clearance of soluble forms of Ab by insulin degrading enzyme as demonstrated in in vitro assays. In microglia, apoliporoteins ApoE and ApoA1 accelerate the proteolytic clearance of soluble Ab following its uptake by micropinocytosis. The internalized Ab peptides by are trafficked in endolytic vesicles to the lysosome where they are degraded, principally by neprilysin. The reduction in levels of soluble Ab in the brain is associated with the rapid reversal of cognitive, social, and olfactory deficits and rapidly improved neural circuit function. Thus, nuclear receptor activation stimulates physiological Aβ clearance mechanisms resulting in the very rapid reversal of a broad range of Aβ-induced deficits including improved memory and cognition. These findings suggest nuclear receptor agonists may be of utility for developing therapeutics for Alzheimer’s disease and its prodromal states.