Microglia heterogeneity in vascular dementia pathology

Microglia exhibit remarkable phenotypic heterogeneity and functional plasticity across brain regions, time, and disease states. In vascular dementia (VaD)—the second most common dementia—cerebrovascular pathology drives distinct microglial activation states. This review synthesizes current understanding of microglial phenotypes in neurological disease, focusing on their contributions to VaD following vascular insults such as chronic cerebral hypoperfusion and stroke. Key VaD-associated phenotypes are described, including spatially segregated subsets in ischemic territories (ICAM and IPAM microglia), TREM1 + -activated microglia in hemorrhagic foci, and cytokine-responsive microglia (CRM) identified in human VaD brain. The molecular drivers of this heterogeneity are discussed, arguing for moving beyond the reductive M1/M2 dichotomy. The broader significance lies in a proposed framework for microglia-targeted therapeutic strategies, encompassing precision immunomodulation, antibody-mediated approaches, and in situ cellular reprogramming as promising avenues for future intervention.