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The interaction of A\u03b2 with the receptor for advanced glycation endproducts (RAGE) facilitates cerebral uptake of A\u03b2 and exacerbates its neurotoxicity and neuroinflammation, further augmenting BACE1 expression. Given the limitations of previous BACE1 inhibition efforts, the study explores reducing BACE1 expression to mitigate AD pathology. The research reveals that the anticancer agent 6\u2010thioguanosine (6\u2010TG) markedly diminishes BACE1 expression without eliciting cytotoxicity while enhancing microglial phagocytic activity, and ameliorate cognitive impairments with reducing A\u03b2 accumulation in AD mice. Leveraging advanced deep learning\u2010based tool for target identification, and corroborating with surface plasmon resonance assays, it is elucidated that 6\u2010TG directly interacts with RAGE, modulating BACE1 expression through the JAK2\u2010STAT1 pathway and elevating soluble RAGE (sRAGE) levels in the brain. 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