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Based on multimodal clinical evidence showing that cerebrovascular dysregulation can precede amyloid-\u03b2 accumulation, this commentary emphasizes three converging lines: (1) hippocampal blood\u2013brain barrier breakdown as an early, potentially amyloid-\/tau-independent event, (2) vascular-first\/parallel two-hit frameworks linking vascular risk factors to subsequent proteinopathy, and (3) early neurovascular coupling failure and chronic hypoperfusion as upstream drivers. 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