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Sleeve gastrectomy (SG) is among the most effective metabolic interventions available, yet its impact on AD progression remains poorly understood. We hypothesized that SG performed early in life would improve metabolic health, attenuate AD pathology, and preserve cognition in a transgenic AD mouse model. Five\u2010week\u2010old female 3xTg\u2010AD mice were preconditioned on a Western diet (WD) to induce obesity and glucose intolerance, then randomized to SG or sham surgery and maintained on either Control or continued WD for 12\u2009months. Metabolic phenotyping, body composition, and cognitive assessments (Novel Object Recognition, Barnes Maze, Fear Conditioning) were performed longitudinally, with histological and molecular brain analysis at endpoint. Under Control\u2010fed conditions, SG reduced fat mass and improved peripheral insulin sensitivity independent of food intake. These changes were accompanied by reduced cortical A\u03b2 plaque burden and attenuated astrocytic (GFAP) and microglial (IBA1) activation, specifically in the cortex. Mechanistically, SG altered the insulin signaling\u2010autophagy axis in a region\u2010specific manner, with increased pAKT and suppressed ATG5\/ATG7\/ATG16L1 in the cortex. Under persistent WD, SG improved glucose homeostasis, reduced fat mass, lowered frailty, and rescued short\u2010 and long\u2010term spatial memory deficits in the Barnes maze, accompanied by reduced cortical A\u03b2 burden. Collectively, these findings provide the first preclinical evidence that SG attenuates AD progression through a brain insulin signaling\u2010autophagy axis, supporting metabolic surgery as a promising disease\u2010modifying intervention for AD prevention in individuals with obesity.<\/jats:p>","DOI":"10.1111\/acel.70767","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T14:42:02Z","timestamp":1791902522000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sleeve Gastrectomy Improves Metabolic Health, Cognition, and Alzheimer's Disease Pathology in\n                    <scp>3xTG<\/scp>\n                    Mice"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3719-5991","authenticated-orcid":false,"given":"Reji","family":"Babygirija","sequence":"first","affiliation":[{"name":"Wisconsin Surgical Laboratory in Metabolism, Department of Surgery University of Wisconsin\u2010Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia A.","family":"Illiano","sequence":"additional","affiliation":[{"name":"Wisconsin Surgical Laboratory in Metabolism, Department of Surgery University of Wisconsin\u2010Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8493-1416","authenticated-orcid":false,"given":"Michelle M.","family":"Sonsalla","sequence":"additional","affiliation":[{"name":"William S. 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Middleton Memorial Veterans Hospital  Madison Wisconsin USA"},{"name":"Department of Medicine University of Wisconsin\u2010Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3021-3993","authenticated-orcid":false,"given":"Justin M.","family":"Wolter","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics University of Wisconsin\u2010Madison  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0079-4467","authenticated-orcid":false,"given":"Dudley W.","family":"Lamming","sequence":"additional","affiliation":[{"name":"William S. Middleton Memorial Veterans Hospital  Madison Wisconsin USA"},{"name":"Department of Medicine University of Wisconsin\u2010Madison  Madison Wisconsin USA"},{"name":"University of Wisconsin\u2010Madison Comprehensive Diabetes Center  Madison Wisconsin USA"},{"name":"Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5588-1632","authenticated-orcid":false,"given":"David A.","family":"Harris","sequence":"additional","affiliation":[{"name":"Wisconsin Surgical Laboratory in Metabolism, Department of Surgery University of Wisconsin\u2010Madison  Madison Wisconsin USA"},{"name":"William S. 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