Alzheimer’s disease is the most common incurable form of dementia affecting 50 million individuals worldwide. Apolipoprotein E4 (APOE4) is the strongest genetic risk factor that is directly linked to its pathogenesis. ApoE is a cholesterol- and lipid-carrier protein that has been implicated in Alzheimer’s disease, aging, and other neurological disorders. Isoform-dependent effect on amyloid accumulation and clearance have been found in humans and mice with APOE4 being detrimental. Haploinsufficiency of ApoE4 and possibly ApoE3 decreases amyloid pathology. Low Density Lipoprotein Receptor (LDLR) plays an important role in the endocytosis of ApoE proteins. LDLR overexpression has been found to decrease ApoE levels and inhibit amyloid formation. Additionally, ApoE’s role in lipidation influences Alzheimer’s pathogenesis. ATP-binding cassette transporter A1 (AbcA1) protein transfers cellular cholesterol onto extracellular lipid-poor apolipoproteins. Overexpression of ABCA1 gene has also been found to inhibit amyloid formation. Therefore, we set out to develop small organic molecules that can increase AbcA1 and/or Ldlr while decreasing ApoE protein levels. Such compounds would likely reduce and clear amyloid plaque deposition in affected brains and provide therapeutic benefit in Alzheimer’s disease. Five triarylmethyl amine (TAMA) small molecules emerged as first leads decreasing ApoE protein level (>30% reduction in the human astrocytoma brain cell line, analyzed using ELISA). The mechanism of action of the TAMA pharmacophore was via LXR antagonism. Structure-Activity Relationship (SAR) studies on the TAMA pharmacophore in five phases of focused libraries, identified five drug-like tertiaryl sulfonamides and aryl amines as new leads. They not only decreased ApoE levels in vitro, but also increased AbcA1/Ldlr protein levels validated by concentration-dependent studies. Three chiral leads in pure R/S forms had disproportionate effects on ApoE and AbcA1 raising the possibility of multiple targets. One of the 8 leads, compound 127 modulated the target proteins in the transgenic mice brains in preliminary in vivo studies. The successful in vivo efficacy of 127 validates its ability to pass the blood-brain barrier (BBB). Preliminary in vitro toxicological experiments revealed all the 8 lead compounds to be not toxic. The SuRE support will enable PI and his undergraduate/graduate research team to utilize the TAMA pharmacophore with critical appendages identified in newer and more potent sulfonamide leads to generate new and novel scaffolds-based leads. These scaffolds are expected to be lighter, drug-like, chemically and pharmacokinetically stable, and less lipophilic. PI aims at performing chemical synthesis and biological screening in his lab with the guidance of a committed consultant.