From diabetic foot to dementia: A neurovascular continuum linking systemic diabetic vasculopathy, cerebral small vessel disease, and glymphatic dysfunction.

Diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), is increasingly recognized as a major risk factor for cognitive decline and dementia. Epidemiological studies consistently demonstrate that individuals with diabetes exhibit a significantly elevated risk of both vascular cognitive impairment and Alzheimer's disease [1,2]. Beyond hyperglycemia, systemic vascular dysfunction has emerged as a central mechanism underlying diabetes-related brain injury. Diabetes induces widespread vascular alterations, including endothelial dysfunction, arterial stiffening, oxidative stress, and chronic low-grade inflammation [3,4]. These processes affect both peripheral and cerebral circulation and may contribute to the development of cerebral small vessel disease (CSVD), a major substrate of cognitive decline [10-12]. Increased arterial stiffness may impair the Windkessel effect and facilitate the transmission of excessive pulsatile energy into fragile cerebral perforating arteries, thereby promoting microvascular injury and white matter damage [13-17]. In addition, diabetes-associated disruption of the neurovascular unit (NVU) may lead to blood-brain barrier dysfunction, neuroinflammation, and neuronal injury [20-30]. Impairment of the glymphatic system responsible for the clearance of metabolic waste products such as amyloid-β and tau may further contribute to neurodegenerative processes [31-41]. In this review, we propose a "systemic vascular continuum" linking peripheral diabetic vasculopathy, cerebral small vessel disease, neurovascular unit dysfunction, and glymphatic impairment. Within this framework, diabetic foot ulcer (DFU) is presented as a clinically visible peripheral phenotype and surrogate marker of advanced systemic vascular injury rather than a direct causal factor [5-9]. This integrative model provides a conceptual framework for understanding diabetes-associated cognitive impairment and highlights vascular-targeted preventive and therapeutic strategies as promising approaches for risk stratification and intervention.