Abstract

Emerging evidence implicates metabolic dysfunction as a key contributor to Alzheimer's disease (AD) pathogenesis. Fructose, a major component of modern diets, promotes systemic metabolic alterations; however, its direct impact on AD-related brain dysfunction remains poorly defined. Here, we investigated the effects of short-term fructose consumption on systemic metabolism, brain glucose handling, and cognitive performance in APP/PS1 transgenic mice. Six-month-old asymptomatic male mice received 15% fructose in drinking water for eight weeks, while controls received plain water. Fructose-fed APP/PS1 mice developed metabolic alterations consistent with early metabolic syndrome, including increased fasting glucose and dyslipidemia. These changes were accompanied by reduced cerebral glucose utilization, increased A beta(42) accumulation, and impaired cognitive performance. In parallel, fructose intake enhanced neuroinflammatory markers, suggesting a coordinated disruption of metabolic and inflammatory pathways in the brain. Collectively, these findings support the idea that fructose consumption may exacerbate Alzheimer-like alterations linking systemic metabolic dysfunction to impaired brain glucose metabolism and neuroinflammation. This study provides mechanistic evidence supporting a role for dietary fructose as a modifiable risk factor in AD vulnerability.