Caveolin-1 at the Crossroads of Diabetes and Alzheimer’s Disease: New Mechanisms, Biomarkers, and Therapeutic Opportunities

Type 2 diabetes mellitus (T2D) is increasingly recognized as a major risk factor for Alzheimer’s disease (AD), supporting the concept that chronic metabolic dysfunction contributes to neurodegeneration. Recent advances have identified caveolin-1 (CAV-1), the principal structural protein of caveolae, as an important regulator of insulin signaling, lipid metabolism, mitochondrial homeostasis, neurovascular integrity, and amyloid precursor protein processing. Since our previous review published in 2020, substantial evidence has demonstrated that altered CAV-1 expression and function are associated with AD-related pathology under diabetic conditions through multiple mechanisms, including endothelial dysfunction, impaired brain insulin signaling, disruption of mitochondria–endoplasmic reticulum contact sites (MERCSs), neuroinflammation, mitochondrial dysfunction, and defective autophagy. Experimental studies further show that restoring neuronal or endothelial CAV-1 expression improves insulin signaling, preserves synaptic function, attenuates amyloid pathology, and ameliorates cognitive decline in preclinical models. This review summarizes recent advances in understanding of the CAV-1-dependent mechanisms linking T2D and AD and discusses the emerging potential of CAV-1 as a biomarker and therapeutic target for diabetes-associated neurodegeneration. Collectively, current evidence identifies CAV-1 as a central molecular hub integrating metabolic, vascular, and neurodegenerative pathways and supports its further investigation as a promising therapeutic target.