Myelin, the intricate lipid-rich sheath enwrapping neuronal axons, has undergone a profound conceptual evolution. Once considered a static insulator whose primary function was to enable saltatory conduction, it is now recognized as a dynamic, plastic, and metabolically active component of the central nervous system (CNS). This plasticity, termed “adaptive myelination,” is fundamental to higher cognitive functions, neural network synchronization, and the lifelong metabolic support of axons. A compelling and convergent body of evidence from advanced neuroimaging, transcriptomic analyses, and preclinical models now identifies myelin dysfunction as a critical pathophysiological hub across a spectrum of conditions, including normative aging, Alzheimer’s disease (AD), multiple sclerosis (MS), major depressive disorder, and post-injury states. Critically, in AD, myelin loss precedes canonical pathologies like amyloid deposition challenging the primacy of the amyloid cascade hypothesis and positioning myelin failure as an upstream driver of neurodegeneration. The emerging paradigm shift is that myelin integrity is not a passive bystander but a central mediator of brain health. This review synthesizes cutting-edge evidence (2023-2025) demonstrating that pharmacological and epigenetic strategies to enhance remyelination using compounds such as clemastine, bazedoxifene, and the novel agent ESI1 can rescue cognitive and motor deficits. In parallel, the application of artificial intelligence to neuroimaging has yielded MRI-based brain age (BAMRI) metrics, which reveal that successful remyelination is associated with a measurable “rejuvenation” of the brain’s structural phenotype. We argue that targeting the oligodendrocyte lineage and myelin integrity represents a transformative, transdiagnostic therapeutic strategy, moving the field from symptomatic management toward true CNS restoration and resilience.
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