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We developed a novel, chemically tailored MALDI workflow that enables simultaneous, spatially resolved detection of nearly 30 FFAs alongside over 100 complex lipid species within the same tissue section. Applying this approach to a transgenic AD mouse model across brain regions and disease stages, and combining it with single-plaque microenvironment analysis (SPMA) that treats each plaque as an individual analytical object, we uncover two previously inaccessible dimensions of plaque-associated lipid biology. FFA distributions form highly structured spatial compartments reflecting regional cytoarchitecture, with distinct enrichment of saturated, monounsaturated, and polyunsaturated species across cortical layers. Within A\u03b2 plaques, nearly 75% of detected FFAs are significantly remodeled, with reciprocal enrichment of short saturated and highly unsaturated species alongside depletion of long-chain monounsaturated FFAs. This pattern is consistent with concurrent disruption of ELOVL-mediated elongation and FADS-mediated desaturation, including opposing enrichment of pro-inflammatory arachidonic acid and pro-resolving docosahexaenoic acid. Machine learning of single-plaque profiles reveals that FFA composition alone classifies plaque age with high accuracy, demonstrating that lipid remodeling continues after A\u03b2 peptide composition has stabilized. Together, these findings establish spatial FFA profiling as a new analytical dimension in neurodegeneration research, revealing that A\u03b2 plaques are dynamic lipid-metabolic microenvironments that continue to remodel long after A\u03b2 deposition has stabilized.<\/jats:p>","DOI":"10.1021\/jacsau.6c00649","type":"journal-article","created":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T13:01:45Z","timestamp":1783774905000},"page":"4153-4165","source":"Crossref","is-referenced-by-count":0,"title":["Spatially Resolved\nFree Fatty Acid Profiling Reveals\nRegion- and Age-Dependent Remodeling of Alzheimer\u2019s Disease\nPlaques"],"prefix":"10.1021","volume":"6","author":[{"given":"Sona","family":"Hakhverdyan","sequence":"first","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, SE-75237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofie","family":"Hansson","sequence":"additional","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, SE-75237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Kadej","sequence":"additional","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, SE-75237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia B.","family":"Orlovsky","sequence":"additional","affiliation":[{"name":"University of Illinois Chicago , , , ,","place":["Chicago, Illinois, United States, 60607"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siarhei","family":"Hladkou","sequence":"additional","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, SE-75237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birger","family":"Viirman","sequence":"additional","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, SE-75237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Nilsson","sequence":"additional","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, SE-75123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Lord","sequence":"additional","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, SE-75123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3541-3361","authenticated-orcid":true,"given":"Stephanie M.","family":"Cologna","sequence":"additional","affiliation":[{"name":"University of Illinois Chicago , , , ,","place":["Chicago, Illinois, United States, 60607"]},{"name":"University of Illinois Chicago , , , ,","place":["Chicago, Illinois, United States, 60607"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7005-3322","authenticated-orcid":true,"given":"Justin T.","family":"Mohr","sequence":"additional","affiliation":[{"name":"University of Illinois Chicago , , , ,","place":["Chicago, Illinois, United States, 60607"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stina","family":"Syva\u0308nen","sequence":"additional","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, SE-75237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4062-7743","authenticated-orcid":true,"given":"Per E.","family":"Andre\u0301n","sequence":"additional","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, SE-75123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3096-3604","authenticated-orcid":true,"given":"Wojciech","family":"Michno","sequence":"additional","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, SE-75237"]},{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, SE-752 37"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,11]]},"reference":[{"key":"2026072709070993700_cit1","doi-asserted-by":"publisher","first-page":"3708","DOI":"10.1016\/j.molcel.2021.08.027","article-title":"Lipid metabolism in\nsickness and in health: Emerging regulators of lipotoxicity","volume":"81","author":"Yoon","year":"2021","journal-title":"Mol. 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Neurosci."},{"key":"2026072709070993700_cit16","doi-asserted-by":"publisher","first-page":"8130","DOI":"10.1021\/acs.analchem.8b01361","article-title":"Multimodal Chemical\nImaging of Amyloid Plaque Polymorphism Reveals A\u03b2 Aggregation\nDependent Anionic Lipid Accumulations and Metabolism","volume":"90","author":"Michno","year":"2018","journal-title":"Anal. Chem."},{"key":"2026072709070993700_cit17","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1111\/jnc.15557","article-title":"Structural amyloid plaque\npolymorphism is associated with distinct lipid accumulations revealed\nby trapped ion mobility mass spectrometry imaging","volume":"160","author":"Michno","year":"2022","journal-title":"J. Neurochem."},{"key":"2026072709070993700_cit18","doi-asserted-by":"publisher","first-page":"9799","DOI":"10.1021\/acs.analchem.3c05557","article-title":"Integrative\nSingle-Plaque Analysis Reveals Signature A\u03b2 and Lipid Profiles\nin the Alzheimer\u2019s Brain","volume":"96","author":"Enzlein","year":"2024","journal-title":"Anal. Chem."},{"key":"2026072709070993700_cit19","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1016\/j.bbapap.2018.09.010","article-title":"GM1 locates\nto mature amyloid structures implicating a prominent role for glycolipid-protein\ninteractions in Alzheimer pathology","volume":"1867","author":"Michno","year":"2019","journal-title":"Biochim.\nBiophys. Acta, Proteins Proteomics"},{"key":"2026072709070993700_cit20","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1021\/acschemneuro.4c00006","article-title":"Spatial Neurolipidomics\nat the Single Amyloid-\u03b2 Plaque Level in Postmortem Human Alzheimer\u2019s\nDisease Brain","volume":"15","author":"Michno","year":"2024","journal-title":"ACS Chem. Neurosci."},{"key":"2026072709070993700_cit21","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1021\/acschemneuro.6b00391","article-title":"Delineating Amyloid\nPlaque Associated Neuronal Sphingolipids in Transgenic Alzheimer\u2019s\nDisease Mice (tgArcSwe) Using MALDI Imaging Mass Spectrometry","volume":"8","author":"Kaya","year":"2017","journal-title":"ACS Chem. Neurosci."},{"key":"2026072709070993700_cit22","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.16306","article-title":"Unsaturated Fatty Acids\nAre Decreased in A\u03b2 Plaques in Alzheimer\u2019s Disease","volume":"169","author":"Ro\u0308hr","year":"2025","journal-title":"J. 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Neurochem."},{"key":"2026072709070993700_cit28","doi-asserted-by":"publisher","first-page":"6719","DOI":"10.1074\/jbc.RA118.006604","article-title":"Pyroglutamation of amyloid-\u03b2x-42\n(A\u03b2x-42) followed by A\u03b21\u201340 deposition underlies\nplaque polymorphism in progressing Alzheimer\u2019s disease pathology","volume":"294","author":"Michno","year":"2019","journal-title":"J. Biol. Chem."},{"issue":"25","key":"2026072709070993700_cit29","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abg4855","article-title":"Following\nspatial A\u03b2\naggregation dynamics in evolving Alzheimer\u2019s disease pathology\nby imaging stable isotope labeling kinetics","volume":"7","author":"Michno","year":"2021","journal-title":"Sci. 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Neurosci."},{"key":"2026072709070993700_cit35","doi-asserted-by":"publisher","DOI":"10.1016\/j.xinn.2022.100360","article-title":"Myelin lipid\nmetabolism and its role\nin myelination and myelin maintenance","volume":"4","author":"Barnes-Ve\u0301lez","year":"2023","journal-title":"Innovation"},{"key":"2026072709070993700_cit36","doi-asserted-by":"publisher","DOI":"10.3390\/cells9040812","article-title":"Myelin Fat\nFacts: An Overview of\nLipids and Fatty Acid Metabolism","volume":"9","author":"Poitelon","year":"2020","journal-title":"Cells"},{"key":"2026072709070993700_cit37","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1038\/nrn3820","article-title":"Polyunsaturated fatty acids and their metabolites in\nbrain function and disease","volume":"15","author":"Bazinet","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"2026072709070993700_cit38","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1006\/nbdi.1996.0005","article-title":"Cytosolic Phospholipase\nA2(cPLA2) Immunoreactivity Is Elevated in Alzheimer\u2019s Disease\nBrain","volume":"3","author":"Stephenson","year":"1996","journal-title":"Neurobiol. Dis."},{"key":"2026072709070993700_cit39","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-025-02214-6","article-title":"Evidence for cPLA2 activation\nin Alzheimer\u2019s disease synaptic pathology","volume":"14","author":"Ma","year":"2026","journal-title":"Acta Neuropathol. Commun."},{"key":"2026072709070993700_cit40","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9121812","article-title":"Epigenomics\nand Lipidomics Integration in Alzheimer Disease: Pathways Involved\nin Early Stages","volume":"9","author":"Pen\u0303a-Bautista","year":"2021","journal-title":"Biomedicines"},{"key":"2026072709070993700_cit41","doi-asserted-by":"publisher","DOI":"10.1016\/j.plefa.2020.102159","article-title":"Genetic variants in\nFADS1 and ELOVL2 increase level of arachidonic acid and the risk of\nAlzheimer\u2019s disease in the Tunisian population","volume":"160","author":"Hammouda","year":"2020","journal-title":"Prostaglandins, Leukotrienes Essent. Fatty Acids"},{"key":"2026072709070993700_cit42","doi-asserted-by":"publisher","DOI":"10.3390\/genes15060810","article-title":"Multifactor\nAnalyses of Frontal Cortex Lipids in the APP\/PS1Model of Familial\nAlzheimer\u2019s Disease Reveal Anomalies in Responses to Dietary\nn-3 PUFA and Estrogenic Treatments","volume":"15","author":"Di\u0301az","year":"2024","journal-title":"Genes"},{"key":"2026072709070993700_cit43","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1038\/s41586-024-07606-7","article-title":"Single-cell multiregion\ndissection of Alzheimer\u2019s disease","volume":"632","author":"Mathys","year":"2024","journal-title":"Nature"},{"key":"2026072709070993700_cit44","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-61497-4","article-title":"Synaptic loss pattern\nis constrained by brain connectome and modulated by phosphorylated\ntau in Alzheimer\u2019s disease","volume":"16","author":"Luan","year":"2025","journal-title":"Nat. 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