Despite substantial research and drug discovery efforts, Alzheimer's Disease (AD) remains the sixth leading cause of death in the United States, underscoring the urgent need for novel therapeutic targets. A mutation in the clusterin (CLU) gene that hinders expression of the cyto-protective secreted isoform of clusterin (sCLU) that affects the aggregation and clearance of two key proteins implicated in AD, Aβ and tau, is the third most significant genetic risk factor for late-onset AD. Here, we present findings from our drug discovery program to identify small molecules that enhance sCLU levels and assess their impact on AD pathology and cognition in a murine model of AD. A high-throughput screening campaign identified two classes of epigenetic modulators that increase sCLU levels with subsequent medicinal chemistry efforts leading to bromodomain and extra-terminal (BET) inhibitor new chemical entities (NCEs) with enhanced potency, drug-like properties, and oral brain bioavailability. The lead candidate NCE, DDL-357, increased brain sCLU in the murine ApoE4TR-5XFAD model of AD in a subchronic study. In a follow-up chronic study in the murine 3xTg-AD model, DDL-357 reduced phospho-tau in brain and led to improvements in mouse performance and memory in the Barnes maze testing paradigm. Proteomic analysis of brain tissue from both AD models revealed changes in proteins involved in mitochondrial function and synaptic plasticity. These findings reveal the potential of sCLU enhancement as a target for therapeutic development in AD and support the continued development of the preclinical lead candidate.