Calcium dysregulation in neurovascular function in Alzheimer's disease: mechanisms, therapeutic targets

Neurovascular dysfunction, characterized by impaired cerebral blood flow (CBF) autoregulation and neurovascular coupling (NVC), represents a critical upstream facilitator of Alzheimer's disease (AD) that precedes overt cognitive decline. While traditional therapeutic strategies that focus strictly on amyloid β clearance have achieved limited long-term clinical efficacy, targeting the mechanisms governing neurovascular uncoupling offers a promising frontier. Calcium ions (Ca²⁺) serve as the quintessential second messenger, linking neuronal metabolic demand to real-time microvascular responsiveness within the neurovascular unit (NVU). In AD, this tightly coordinated Ca²⁺ homeostatic network undergoes a widespread, cell-specific, and stage-dependent collapse. Here, we systematically summarize physiological Ca²⁺ handling mediated by plasma membrane channels, transporters, and intracellular organelles in the cerebral vasculature. We further dissect cell type-specific Ca²⁺ dysregulation throughout the NVU during AD progression, including biphasic alterations in neurons, astrocytes, and endothelial cells, as well as progressive Ca²⁺ overload in pericytes and vascular smooth muscle cells. Additionally, we review repurposed and novel pharmacological agents targeting Ca²⁺ pathways to restore NVC and CBF homeostasis, as well as cell type-specific therapeutic challenges. Finally, we discuss unresolved controversies regarding the causal relationship between Ca²⁺ dysfunction and AD protein pathology and highlight future directions for early intervention. This review emphasizes Ca²⁺ signaling as a promising therapeutic target to break the vicious cycle of neurovascular impairment and neurodegeneration in AD.