ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in Alzheimer's disease (AD) mouse models. The study shows that oral administration of the RXR agonist bexarotene enhances the clearance of soluble β-amyloid (Aβ) in a ApoE-dependent manner. Within hours of treatment, Aβ levels in brain interstitial fluid (ISF) decreased significantly, with a 25% reduction by 24 hours. After 72 hours, Aβ plaque area was reduced by more than 50%. Bexarotene also reversed cognitive, social, and olfactory deficits and improved neural circuit function. ApoE is crucial for Aβ clearance, and its expression is regulated by nuclear receptors PPARγ and LXR, which form heterodimers with RXR. Bexarotene activates these receptors, inducing ApoE expression and promoting Aβ clearance and microglial phagocytosis. Bexarotene treatment of primary microglia and astrocytes increased ApoE, ABCA1, and ABCG1 expression, and enhanced degradation of soluble Aβ. In APP/PS1 mice, bexarotene treatment significantly reduced soluble and insoluble Aβ levels, with a 75% reduction in total and thioflavin-S positive plaques after 14 days. It also restored nest construction behavior and improved olfactory function. Chronic bexarotene treatment for 3 months reduced Aβ levels by about 30% and improved hippocampal function. Bexarotene treatment restored cognitive and memory functions in APP/PS1 mice, as assessed by contextual fear conditioning. It also improved odor-evoked cortical local field potentials, indicating restored neural circuit function. These results suggest that RXR agonists may be therapeutically useful for AD and its precursor stages. The study highlights the importance of ApoE in Aβ clearance and the potential of RXR agonists as a treatment for AD.ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in Alzheimer's disease (AD) mouse models. The study shows that oral administration of the RXR agonist bexarotene enhances the clearance of soluble β-amyloid (Aβ) in a ApoE-dependent manner. Within hours of treatment, Aβ levels in brain interstitial fluid (ISF) decreased significantly, with a 25% reduction by 24 hours. After 72 hours, Aβ plaque area was reduced by more than 50%. Bexarotene also reversed cognitive, social, and olfactory deficits and improved neural circuit function. ApoE is crucial for Aβ clearance, and its expression is regulated by nuclear receptors PPARγ and LXR, which form heterodimers with RXR. Bexarotene activates these receptors, inducing ApoE expression and promoting Aβ clearance and microglial phagocytosis. Bexarotene treatment of primary microglia and astrocytes increased ApoE, ABCA1, and ABCG1 expression, and enhanced degradation of soluble Aβ. In APP/PS1 mice, bexarotene treatment significantly reduced soluble and insoluble Aβ levels, with a 75% reduction in total and thioflavin-S positive plaques after 14 days. It also restored nest construction behavior and improved olfactory function. Chronic bexarotene treatment for 3 months reduced Aβ levels by about 30% and improved hippocampal function. Bexarotene treatment restored cognitive and memory functions in APP/PS1 mice, as assessed by contextual fear conditioning. It also improved odor-evoked cortical local field potentials, indicating restored neural circuit function. These results suggest that RXR agonists may be therapeutically useful for AD and its precursor stages. The study highlights the importance of ApoE in Aβ clearance and the potential of RXR agonists as a treatment for AD.