Sleeve Gastrectomy Improves Metabolic Health, Cognition, and Alzheimer's Disease Pathology in 3xTG Mice

ABSTRACT Obesity and diabetes are well‐established risk factors for Alzheimer's disease (AD), implicating metabolic dysfunction in AD pathogenesis. 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‐week‐old female 3xTg‐AD 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 months. 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‐fed conditions, SG reduced fat mass and improved peripheral insulin sensitivity independent of food intake. These changes were accompanied by reduced cortical Aβ plaque burden and attenuated astrocytic (GFAP) and microglial (IBA1) activation, specifically in the cortex. Mechanistically, SG altered the insulin signaling‐autophagy axis in a region‐specific 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‐ and long‐term spatial memory deficits in the Barnes maze, accompanied by reduced cortical Aβ burden. Collectively, these findings provide the first preclinical evidence that SG attenuates AD progression through a brain insulin signaling‐autophagy axis, supporting metabolic surgery as a promising disease‐modifying intervention for AD prevention in individuals with obesity.