This article presents research on Alzheimer’s disease (AD) pathogenesis using multiscale proteomic network modeling that integrates extensive proteomic and genetic data from vulnerable brain regions like the parahippocampal gyrus. Researchers identified hundreds of co-expressed protein modules and a key glia-neuron subnetwork strongly linked to AD progression. Through Bayesian causal network analysis, the study pinpointed key driver proteins (KDPs) of the disease, including AHNAK, an astrocytic driver. Experimental validation using human induced pluripotent stem cell (iPSC)-derived brain cells confirmed that the downregulation of AHNAK significantly reduced pTau and Aβ levels and rescued neurodegeneration, establishing AHNAK as a promising therapeutic target. These findings offer a systematic foundation for understanding molecular mechanisms and developing next-generation AD treatments.
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