Metabolic stress and age drive inflammation and cognitive decline in mice and humans

Abstract INTRODUCTION Metabolic stressors (obesity, metabolic syndrome, prediabetes, and type 2 diabetes [T2D]) increase the risk of cognitive impairment (CI), including Alzheimer's disease (AD). Immune system dysregulation and inflammation, particularly microglial mediated, may underlie this risk, but mechanisms remain unclear. METHODS Using a high‐fat diet‐fed (HFD) model, we assessed longitudinal metabolism and cognition, and terminal inflammation and brain spatial transcriptomics. Additionally, we performed hippocampal spatial transcriptomics and single‐cell RNA sequencing of post mortem tissue from AD and T2D human subjects versus controls. RESULTS 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 ( SPP1 ), a pro‐inflammatory gene associated with AD. DISCUSSION 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 SPP1 , in CI. Highlights Metabolic stress causes persistent metabolic and cognitive impairments in mice. Murine and human brain spatial transcriptomics align and indicate a pro‐inflammatory milieu. Transcriptomic data indicate a role for microglial‐mediated inflammatory mechanisms. Secreted phosphoprotein 1 emerged as a potential target of interest in metabolically driven cognitive impairment.