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White Matter Hyperintensities Mediate the Negative Impact of HbA1c Levels on Cognitive Function

Rudolph Johnstone1, Ida Rangus2, Natalie Busby2

  • 1School of Medicine Columbia, University of South Carolina, 6311 Garners Ferry Rd, Columbia, SC 29209, USA.

Brain Sciences
|July 29, 2025
PubMed
Abstract

Insights

Type 2 diabetes impairs cognition, potentially via white matter hyperintensities (WMHs). These WMHs partially explain the link between high hemoglobin A1c (HbA1c) and lower cognitive scores, suggesting a vascular mechanism.

Area of Science:

  • Neuroscience
  • Endocrinology
  • Gerontology

Background:

  • Type 2 diabetes is associated with cognitive dysfunction, with unclear underlying mechanisms.
  • White matter hyperintensities (WMHs) are prevalent in diabetes and linked to vascular brain injury.

Purpose of the Study:

  • To investigate if WMH burden mediates the relationship between hemoglobin A1c (HbA1c) levels and cognitive function.
  • To explore potential microvascular mechanisms in diabetes-related cognitive impairment.

Main Methods:

  • Quantified WMH load using the Fazekas scale.
  • Performed mediation analysis with HbA1c as the independent variable, Fazekas scale as the mediator, and Montreal Cognitive Assessment (MoCA) scores as the outcome.

Main Results:

  • WMHs partially mediated the association between HbA1c and MoCA scores (indirect effect = -0.224, p = 0.001).
  • WMHs accounted for approximately 15.6% of the total effect of HbA1c on cognition.

Conclusions:

  • WMHs partially mediate the link between elevated blood glucose and cognitive impairment in neurologically healthy adults.
  • Findings support a microvascular pathway contributing to cognitive decline in diabetes.
Keywords:
brain agingcognitive impairmentdementiadiabeteswhite matter hyperintensities

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