The brain’s Extracellular Matrix (ECM) is a unique 3-dimensional macromolecular network implicated in homeostasis, neuronal plasticity, and aging-related cognitive alterations. Based on previous animal studies we hypothesized that neural ECM molecules like the proteoglycan brevican (BCAN) affect cognitive flexibility (CFL) also in humans. We addressed this hypothesis in young and older healthy human subjects by assessing flexibility performance and gray matter volumes (GMV) in dorsal anterior cingulate cortex (dACC), a key structure for cognitive control, together with serum concentrations of ECM molecules.In our study, we examined 83 young (36 male, 47 female, age 18-35, mean age 24.37 ± 4.18 years) and 131 older (50 male, 81 female, age 51-80, mean age 64.21 ± 7.05 years) adults, employing a comprehensive neuropsychological assessment, magnetic resonance imaging (MRI), and enzyme-linked immunosorbent assay (ELISA) measurements.As expected, older adults displayed higher error rates and longer reaction times in CFL-dependent tasks, and decreased total GMV. BCAN serum levels were reduced in older adults and correlated positively with CFL measures and dACC GMV in both age groups. Notably, these associations remained consistent even after controlling for lifestyle factors such as body mass index (BMI), smoking behavior, or physical activity.These findings highlight the importance of neural ECM components for cognitive flexibility in humans and may guide future therapeutic interventions for cognitive decline and neurological disorders within the aging population.