Sleeve gastrectomy improves metabolic health, cognition, and Alzheimer’s Disease pathology in 3xTG mice

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 standard chow 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 analysis of brain tissue at endpoint. Under chow-fed conditions, SG reduced adiposity, improved insulin sensitivity, and decreased cortical Aβ plaque burden, accompanied by attenuated gliosis (GFAP, IBA1) and region-specific, insulin pathway-dependent modulation of autophagy. Under persistent WD, SG improved metabolic health, frailty, spatial cognition, and Aβ pathology, again with corresponding perturbations in autophagy pathway activity. Across all groups, food intake did not differ significantly, indicating that these effects were not secondary to caloric restriction. Collectively, these data suggest that SG engages neuroprotective brain insulin signaling pathways, supporting metabolic surgery as a promising disease-modifying intervention for AD prevention in individuals with obesity.