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This study investigates lipid alterations within these plaques using a novel, label\u2010free, multimodal approach. Combining infrared (IR) imaging, machine learning, laser microdissection (LMD), and flow injection analysis mass spectrometry (FIA\u2010MS), we provide the first comprehensive lipidomic analysis of chemically unaltered A\u03b2 plaques in post\u2010mortem human AD brain tissue. IR imaging revealed decreased lipid unsaturation within plaques, evidenced by a reduction in the alkene (=C\u2010H) stretching vibration band. The high spatial resolution of IR imaging, coupled with machine learning\u2010based plaque detection, enabled precise and label\u2010free extraction of plaques via LMD. Subsequent FIA\u2010MS analysis confirmed a significant increase in short\u2010chain saturated lipids and a concomitant decrease in long\u2010chain unsaturated lipids within plaques compared to the surrounding tissue. These findings highlight a substantial depletion of unsaturated fatty acids (UFAs) in A\u03b2 plaques, suggesting a pivotal role for lipid dysregulation and oxidative stress in AD pathology. This study advances our understanding of the molecular landscape of A\u03b2 plaques and underscores the potential of lipid\u2010based therapeutic strategies in AD.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16306-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.16306","type":"journal-article","created":{"date-parts":[[2025,1,18]],"date-time":"2025-01-18T11:46:23Z","timestamp":1737200783000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Unsaturated Fatty Acids Are Decreased in A\u03b2 Plaques in Alzheimer's 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