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This review aims to explore the connections between diabetes, systemic vascular dysfunction, and cognitive decline. It highlights the role of peripheral diabetic vasculopathy as a marker for systemic vascular injury leading to neurodegeneration.

July 10, 2026Open Access

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

YIYuriko InoueShowa University TOTatsunori OguchiShowa University AIAkio InoueKyoto University

Key Points

This review aims to explore the connections between diabetes, systemic vascular dysfunction, and cognitive decline. It highlights the role of peripheral diabetic vasculopathy as a marker for systemic vascular injury leading to neurodegeneration.
Literature review on the effects of type 2 diabetes on vascular health and cognitive impairment.
Analysis of the relationship between diabetic foot ulcers and systemic vascular conditions.
Discussion on potential vascular-targeted therapies for cognitive decline in diabetes.
Individuals with diabetes show increased risk of vascular cognitive impairment and Alzheimer's disease.
Diabetes causes endothelial dysfunction and chronic inflammation, contributing to cerebral small vessel disease.
Glymphatic dysfunction may impair waste clearance, exacerbating neurodegenerative processes.

Abstract

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.

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