Timing and Duration of Prediabetic Metabolic Dysfunction Differentially Impact Cerebral Perfusion, Vascular Structure, and Behavior.

Obesity is a major risk factor for metabolic dysfunction and cognitive decline, yet the influence of age of onset and sex on neurovascular outcomes remains unclear. We examined how the age at initiation and duration of diet-induced obesity influence metabolism, cognition, and cerebrovascular perfusion in male and female mice. A high-fat diet increased body weight and impaired glucose regulation, particularly in females. Obesity selectively impaired recognition memory while sparing spatial working memory. Cerebrovascular effects were region- and age-specific. Early- and mid-life obesity produced localized perfusion changes despite preserved global cortical blood flow. In contrast, early-life obesity was associated with reduced cortical perfusion and decreased hippocampal vascular complexity, including fewer branch points and smaller vessel diameters. These alterations parallel recognition memory deficits, suggesting a vascular mechanism linking early metabolic stress to cognitive impairment. Together, our findings identify early-life obesity as a critical window of vulnerability for long-term neurovascular and cognitive dysfunction.