Ferritin-positive microglial clusters associate with microvessels and markers of vascular injury in MCI and Alzheimer's disease.

Progressive cognitive decline in Alzheimer's disease is coupled with altered microglial function, and cerebrovascular pathologies. We investigated whether reactive microglia cell clusters and microvascular breakdown spatially overlap in human brain sections impacted by Alzheimer's neuropathology. Immunofluorescence analysis was performed on thick (100-150 μm) autopsy human brain sections of inferior temporal cortex, from controls, individuals with mild cognitive impairment, and Alzheimer's disease. Ferritin-positive microglia clusters and capillary integrity across neuropathological disease stages were assessed. Microglia displayed morphologies representative of reactivity, with ferritin-positive areal density and extent of microglial cell clustering highest in cases with mild cognitive impairment or mid-stage Braak pathology. Localisation of microglia clusters was primarily perivascular and overlapped neuritic plaques. These clusters were proximal to vascular abnormalities, including evidence of endothelial disruption (extravascular lectin-positive staining), capillary thinning, tortuosity, and string vessels. A significant decrease in capillary widths was observed in Alzheimer's disease cases. This data supports a model in which early microglia activation state changes, and their perivascular clustering in response to vascular injury is a precursor to local neuritic tau inclusion development. Progressive microvessel injury may promote neuroinflammation early in disease. These findings highlight the importance of microglial-vascular interactions in the early pathogenesis of AD and underscore the potential for immunovascular biomarkers and interventions targeting early-stage disease.