Brain insulin resistance as a driver of proteinopathy in neurodegeneration: from cell-type-specific mechanisms to targeted therapeutics.

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Neurodegenerative diseases are increasingly linked to systemic metabolic dysfunction, with brain insulin resistance (BIR) positioned as a central mediator. Yet translating this insight into effective therapies has proven remarkably difficult. This review argues that BIR-driven neurodegeneration should be interpreted at two distinct but interconnected levels: cell-type-specific disruption of brain homeostasis by BIR, and the direct, mechanistic role of BIR in driving the proteinopathies that define Alzheimer's and Parkinson's diseases. We first show how BIR produces distinct functional deficits across neurons, astrocytes, microglia, and oligodendrocytes, impairing synaptic plasticity, metabolic coupling, immunometabolic homeostasis, and myelination, resulting in a cellular milieu that favors proteinopathy. We then map molecular pathways through which BIR directly distrubs the metabolism of amyloid-β, tau, and α-synuclein. We further examine how islet amyloid polypeptide cross-seeds cerebral amyloid pathology, suggesting a direct molecular interaction between the peripheral drivers of BIR and protein aggregation. In this framework, BIR functions not as a passive risk factor, but as an active, upstream driver of proteostatic collapse. Cellular dysfunction combined with proteostatic failure, defines the therapeutic target space. We evaluate interventions accordingly, distinguishing those that primarily restore cellular function from those that enhance protein clearance, and those that achieve both. For each strategy, we assess the translational evidence, critically appraising the barriers that have limited their clinical success, including patient heterogeneity, narrow therapeutic windows, and inadequate central nervous system delivery. By integrating cell-type-specific biology with proteostatic mechanisms and a clinically oriented therapeutic framework, this review aims to provide a foundation for multi-target strategies that address the BIR-neurodegeneration axis at its mechanistic roots.

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