Fructose Intake Is Associated with Brain Metabolic Reprogramming and Exacerbation of Alzheimer-like Alterations in APP/PS1 Mice

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 Aβ42 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.