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However, our understanding of how proximity to these Alzheimer\u2019s disease (AD) pathological hallmarks in situ relates to microglial gene expression remains obscure. Here, we utilized high-resolution spatial transcriptomics (ST) via the Xenium platform with a fully customized gene panel to elucidate disease-associated microglial subtypes in tandem with examining metabolic signatures across AD-relevant mouse models and well-characterized human postmortem tissue. Three mouse models were evaluated: PS19, APP\/PS1, and 5xFAD. Analyzing anatomical features across entire hemisections, our approach resolved the distribution of five disease-associated microglial subtypes, while deciphering how proximity to cerebral amyloid plaques influenced transcriptional mediators governing metabolic pathways. We observed robust alterations in glycolytic and cholesterol\/lipid processing pathways in plaque-associated microglia, consistent with a specific switch to glycolysis and lipid-fueled metabolism in the plaque niche. Extending our analysis to human postmortem dorsolateral prefrontal cortex (dlPFC), we identified conserved disease-reactive microglial states, i.e., similar proximity-dependent metabolic shifts around amyloid plaques. Further, integrating spatial transcriptomics with machine-learning approaches revealed novel anatomic domain-specific cellular gene expression profiling features, highlighting differential vulnerabilities of neuronal, glial, and vascular populations near specific microglial subtypes. Together, our findings provide one of the first comprehensive and high-resolution atlas of microglial immunometabolic states across species, anatomical regions, and AD pathological burden.<\/jats:p>","DOI":"10.1101\/2025.05.16.654329","type":"posted-content","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T12:15:17Z","timestamp":1747397717000},"source":"Crossref","is-referenced-by-count":8,"title":["High-Resolution Spatial Profiling of Microglia Reveals Proximity Associated Immunometabolic Reprogramming in Alzheimer\u2019s Disease"],"prefix":"10.64898","author":[{"given":"Kai","family":"Saito","sequence":"first","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle S.","family":"Goulding","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia L.","family":"Nolt","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Kentucky College of Medicine, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia H.","family":"Dimas","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY"},{"name":"Department of Neuroscience, University of Kentucky College of Medicine, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren C.","family":"Moore","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaiah O.","family":"Stevens","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Kentucky College of Medicine, 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