Remodeling of the brain immune microenvironment in Alzheimer's disease: interactions among microglia, astrocytes, complement, and the neurovascular unit.

Alzheimer's disease is defined by amyloid-β deposition and tau pathology, yet comparable pathological burdens do not necessarily correspond to similar cognitive trajectories, regional patterns of injury, or treatment responses. This discordance suggests that the cellular and tissue microenvironment may materially shape disease progression. Genetic studies, single-cell and spatial omics, and human-derived models further indicate that microglia, astrocytes, the complement system, and the neurovascular unit undergo coordinated remodeling during the preclinical phase of AD and influence pathological spread, synaptic injury, and neurodegeneration through intercellular interactions. Remodeling of the brain immune microenvironment is regionally specific, stage dependent, and heterogeneous across cellular states; conventional pro-inflammatory/anti-inflammatory or activated/resting dichotomies therefore fail to capture its dynamics. This review examines the remodeling of the AD brain immune microenvironment through interactions among microglia, astrocytes, complement, and the neurovascular unit, with emphasis on their roles in Aβ and tau pathology, synaptic injury, lipid homeostasis, and vascular dysfunction, and considers the interpretive limits of single-cell and spatial-omics evidence. Current evidence supports a dynamically reconfigured system rather than a uniformly escalating inflammatory response. Therapeutic strategies should move beyond broad anti-inflammatory approaches to preserve effective pathological clearance within appropriate disease windows, limit maladaptive synaptic injury, and restore glial and neurovascular homeostasis.