<p>The parallel rise in obesity and neurological disorders suggests a potential mechanistic link between these two conditions. Midlife obesity is a well-established risk factor for cognitive decline and neurological disorders; however, the underlying mechanisms and cause-and-effect relationship remain poorly defined, in part owing to limited spatiotemporal resolution in existing studies and the absence of a unifying framework. Recent studies have begun to uncover pathways linking obesity to neurodegenerative vulnerability. First, we discuss how obesity induces brain-wide reprogramming across neural, metabolic and vascular systems including neurovascular coupling, blood–brain barrier integrity, cerebrospinal fluid dynamics and myelination. By systematically examining the disparate mechanisms for each condition, a more cohesive picture emerges, revealing progressive neurodegeneration driven by chronic metabolic overload. Lastly, we propose a framework that integrates these different mechanisms with both spatial and temporal specificity.</p>