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Immune system dysregulation and inflammation, particularly microglial mediated, may underlie this risk, but mechanisms remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Using a high\u2010fat diet\u2010fed (HFD) model, we assessed longitudinal metabolism and cognition, and terminal inflammation and brain spatial transcriptomics. Additionally, we performed hippocampal spatial transcriptomics and single\u2010cell RNA sequencing of\n                      <jats:italic>post mortem<\/jats:italic>\n                      tissue from AD and T2D human subjects versus controls.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      HFD induced progressive metabolic and CI with terminal inflammatory changes, and dysmetabolic, neurodegenerative, and inflammatory gene expression profiles, particularly in microglia. AD and T2D human subjects had similar gene expression changes, including in secreted phosphoprotein 1 (\n                      <jats:italic>SPP1<\/jats:italic>\n                      ), a pro\u2010inflammatory gene associated with AD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      These data show that metabolic stressors cause early and progressive CI, with inflammatory changes that promote disease. They also indicate a role for microglia, particularly microglial\n                      <jats:italic>SPP1<\/jats:italic>\n                      , in CI.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Metabolic stress causes persistent metabolic and cognitive impairments in mice.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Murine and human brain spatial transcriptomics align and indicate a pro\u2010inflammatory milieu.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Transcriptomic data indicate a role for microglial\u2010mediated inflammatory mechanisms.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Secreted phosphoprotein 1 emerged as a potential target of interest in metabolically driven cognitive impairment.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70060","type":"journal-article","created":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T07:50:09Z","timestamp":1742457009000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Metabolic stress and age drive inflammation and cognitive decline in mice and humans"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4219-2712","authenticated-orcid":false,"given":"Sarah E.","family":"Elzinga","sequence":"first","affiliation":[{"name":"Department of Neurology 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