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These results show that amyloid clearance is clinically relevant but not sufficient for full restoration of neuroimmune, metabolic, synaptic, and neurovascular balance. Microglia are now seen as central to Alzheimer\u2019s disease susceptibility and progression, existing along dynamic, spatially organized, sex-influenced, and genetically determined continua beyond a simple pro- or anti-inflammatory state. This review calls out three key drivers of microglial dysfunction: the TREM2\u2013APOE lipid-sensing axis, complement-mediated synaptic elimination, and immunometabolic reprogramming\u2014including glycolysis, mitochondrial damage, autophagy failure, NAD+ depletion, and innate immune signaling. We examine natural bioactive compounds, metabolic modulators, and biomimetic nanodelivery as promising, yet currently unproven, strategies for adjusting microglial state. Future therapies should incorporate both pathology removal and microenvironment protection, tailored by disease stage, genetic profile, sex, vascular risk, and microglial state-associated biomarkers.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1843978","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T04:28:13Z","timestamp":1781584093000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Calibrating microglia states in Alzheimer\u2019s disease: decoding immune-metabolic networks and nano-targeted multicomponent therapies"],"prefix":"10.3389","volume":"17","author":[{"given":"Jin Feng","family":"Xing","sequence":"first","affiliation":[{"name":"School of Integrated Traditional Chinese and Western Medicine, Changchun University of Chinese Medicine","place":["Changchun, 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