Abstract
Metabolic dysfunction of insulin resistance (IR) may compromise brain function decades before overt disease. We assessed biomarkers of peripheral and central IR for three years in 125 cognitively intact adults without diabetes or depression (23-61 y) to clarify their relative contributions to trajectories of metabolic and cognitive change. Peripheral IR was quantified by measuring steady-state plasma glucose (SSPG) concentration during the insulin-suppression test and ancillary metabolic indices; central IR was indexed by phosphorylated insulin-receptor-substrate-1 (p-IRS1) in neuron-derived extracellular vesicles (NDEs) isolated from plasma. Mixed-effects models controlling for age, sex and BMI showed that higher baseline SSPG concentration robustly predicted subsequent increases in HOMA-IR and fasting insulin but was unrelated to cognitive outcomes. In contrast, higher baseline NDE p-IRS1 predicted better global cognition (MMSE) over time, an effect strongest in younger participants, yet showed no association with peripheral metabolic change. Participants with concordantly low fasting insulin and C-peptide maintained roughly two-fold higher p-IRS1 than those in the highest tertiles, despite similar trajectories across visits. Neither peripheral nor central IR predicted telomere attrition. Cross-sectionally, p-IRS1 correlated inversely with SSPG concentration, BMI and leptin, suggesting compensatory brain-periphery coupling. These findings indicate that NDE-based markers capture a dimension of brain metabolic vulnerability distinct from classical peripheral measures.