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A central challenge in Alzheimers disease is understanding the mechanism of neuronal secretory dysfunction. By exploiting AI, we reveal how beta-amyloid disrupts key protein interactions within the neuronal secretory machinery. In a combinatorial strategy of reprogramming the neuronal secretory and metabolic components, we established a dual-target therapeutic framework that repairs synaptic and mitochondrial defects to counteract neurodegeneration in Alzheimers.