Blood-Brain Barrier Permeability Is Elevated in Type 2 Diabetes and Obesity: Associations with Cognitive Function and Metabolic Markers

Background Type 2 diabetes (T2D) and obesity are established risk factors for Alzheimer's disease and related dementias, yet the cerebrovascular mechanisms linking metabolic dysfunction to cognitive decline remain poorly understood. Prior human studies relied on gadolinium-based methods to measure blood-brain-barrier (BBB) permeability to larger molecules (~ 550 Da), potentially underestimating subtle BBB disruption. This study aims to assess BBB water permeability in older adults with T2D and obesity using non-contrast WEPCAST MRI, and to evaluate associations between BBB integrity, metabolic markers, and cognitive function. Methods Twenty-eight older adults − 12 with T2D and obesity (BMI ≥ 30 kg/m²) and 16 age- and sex- matched controls - underwent WEPCAST MRI to quantify the BBB permeability measures: permeability-surface area product (PS), water extraction fraction (E) and global cerebral blood flow (CBF), along with T1-Weighted structural MRI acquisition. Cognitive function and fasting blood biomarkers were assessed in all participants. Associations between PS versus metabolic and cognitive function were examined using linear regression adjusted for age and sex. An additional adjustment for statin use was made for hemoglobin A1c (HbA1c) and lipid markers. Results T2D participants exhibited significantly elevated BBB water permeability (PS: P = 0.001, Hedges' g = 1.10) despite preserved CBF. Specifically, higher PS was associated with HbA1c (f² = 0.28, P = 0.016) and lower circulating cholesterol (total cholesterol: f² = 0.49, P = 0.003; LDL: f² = 0.45, P = 0.004; HDL: f² = 0.18, P = 0.053). The T2D group demonstrated lower scores across multiple domains including memory, attention, learning, executive function, and processing speed (g = 0.80–1.42). Higher PS was associated with poorer measures of executive function (P-values < 0.05). Conclusions Older adults with T2D and obesity exhibit elevated BBB water permeability, detectable by non-contrast WEPCAST MRI. Higher BBB water permeability was associated with higher glycemic burden and lower executive function, providing preliminary evidence that BBB permeability may serve as a novel imaging biomarker linking metabolic dysregulation to early cognitive vulnerability in T2D that follows a traditional “frontal-subcortical” pattern.