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

Authors

Yuriko Inoue, Tatsunori Oguchi, Akio Inoue, Mikako Tanaka, Akiko Sasaki, Koji Saito, Hiromitsu Ezure, Naruhito Otsuka

Published in

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. Volume 201. Pages 119681. Jul 07, 2026. Epub Jul 07, 2026.

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.

PMID:
42413140
Bibliographic data and abstract were imported from PubMed on 08 Jul 2026.

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