Ischemic stroke and Alzheimer's disease (AD) are leading causes of neurological disability and cognitive decline, respectively. Although traditionally studied as distinct disorders, growing evidence suggests that both conditions can be understood within a brain-heart disease framework characterized by disrupted oxygen and energy homeostasis. Acute cerebral ischemia can provoke secondary cardiac dysfunction, whereas chronic cardiovascular insufficiency may impair cerebral perfusion, disrupt neurovascular homeostasis, and accelerate cognitive decline. These reciprocal interactions support the concept of a bidirectional brain-heart axis that links neural and cardiac vulnerability. Within this cross-organ stress network, hypoxia-responsive signaling, metabolic reprogramming, mitochondrial dysfunction, neurovascular injury, and systemic inflammation contribute to adaptive and maladaptive responses across multiple organ systems. In this Review, we examine how brain-heart interactions shape responses to acute and chronic neurological injury, with particular emphasis on ischemic stroke and AD as representative models of acute and chronic oxygen-energy stress. We discuss mechanisms of metabolic adaptation, neurovascular remodeling, inflammatory activation, and hypoxia-inducible factor (HIF) signaling across the brain-heart axis, while highlighting evidence from experimental studies, single-cell analyses, and human clinical investigations. By integrating these findings, we propose a systems-level framework that may help explain how acute neurological injury, chronic neurodegeneration, and cardiometabolic stress converge over time and guide the development of more integrated therapeutic strategies. 

Ischemic stroke and Alzheimer's disease (AD) are leading causes of neurological disability and cognitive decline, respectively. Although traditionally studied as distinct disorders, growing evidence suggests that both conditions can be understood within a brain-heart disease framework characterized by disrupted oxygen and energy homeostasis. Acute cerebral ischemia can provoke secondary cardiac dysfunction, whereas chronic cardiovascular insufficiency may impair cerebral perfusion, disrupt neurovascular homeostasis, and accelerate cognitive decline. These reciprocal interactions support the concept of a bidirectional brain-heart axis that links neural and cardiac vulnerability. Within this cross-organ stress network, hypoxia-responsive signaling, metabolic reprogramming, mitochondrial dysfunction, neurovascular injury, and systemic inflammation contribute to adaptive and maladaptive responses across multiple organ systems. In this Review, we examine how brain-heart interactions shape responses to acute and chronic neurological injury, with particular emphasis on ischemic stroke and AD as representative models of acute and chronic oxygen-energy stress. We discuss mechanisms of metabolic adaptation, neurovascular remodeling, inflammatory activation, and hypoxia-inducible factor (HIF) signaling across the brain-heart axis, while highlighting evidence from experimental studies, single-cell analyses, and human clinical investigations. By integrating these findings, we propose a systems-level framework that may help explain how acute neurological injury, chronic neurodegeneration, and cardiometabolic stress converge over time and guide the development of more integrated therapeutic strategies.