Insulin resistance is a central feature of metabolic disorders such as type 2 diabetes (T2D). While studies on this disorder have largely been linked to glucose metabolism and intracellular signaling, recent advances reveal that insulin resistance extends beyond traditional glucose regulatory pathways, impacting multiple organs including the brain, contributing to cognitive dysfunction and neurodegenerative diseases such as Alzheimer's disease (AD). This opinion revisits insulin resistance through molecular, cellular, and systemic perspectives, emphasizing the intersection between peripheral and brain insulin resistance (BIR), the role of the blood-brain barrier (BBB), and emerging biomarkers. Furthermore, we integrate insights from multi-omics and neuroimaging studies to refine our understanding, advocating for a broader perspective that informs early detection and intervention in metabolic and neurodegenerative diseases.