ORIGINAL RESEARCH
Adv. Drug Alcohol Res.
Molecular and biochemical correlates of frontal lobe white matter degeneration in humans with alcohol use disorder
- SM
Suzanne M de la Monte 1,2
- MT
Ming Tong 2,1
- GS
Greg Sutherland 3
1. Brown University, Providence, United States
2. Rhode Island Hospital, Providence, United States
3. The University of Sydney, Sydney, Australia
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Abstract
Background: Alcohol-related brain damage caused by heavy alcohol misuse is associated with cognitive-motor impairment and white matter (WM) degeneration. Oligodendrocytes and myelin are major targets, but the underlying mechanisms remain incompletely characterized, particularly in humans. Purpose: This study investigates the nature of oligodendrocyte dysfunction in anterior frontal lobe tissue from humans with alcohol use disorder (AUD), focusing on molecular and biochemical pathologies that may underlie WM ARBD. Methods: Cores of fresh frozen human postmortem frontal lobe WM from adults with AUD or no history of substance use disorder (N=6/group) were analyzed with duplex enzyme-linked immunosorbent assays, multiplex immunoassays, and multiplex RNA hybridization panels. Results: AUD anterior frontal lobe WM tissue exhibited myelin loss with significant changes in oligodendrocyte/myelin glycoprotein immunoreactivity and mRNA expression, increased glial fibrillary acidic protein, and reduced expression of mRNA transcripts encoding upstream components of the insulin and insulin-like growth factor networks, aspartyl-asparaginyl-β-hydroxylase, and the Notch signaling pathway. In contrast, neuroinflammatory mediators and Alzheimer's disease (AD) biomarkers were largely unaffected. Conclusions: Human AUD anterior frontal lobe WM pathology is accompanied by significant alterations in oligodendrocyte and astrocyte function, with alterations in Notch and insulin/IGF signaling. The findings provide new information on the mechanisms of AUD-mediated WM degeneration as well as potential strategies for diagnosing ARBD in humans.
Summary
Keywords
alcohol, Alcohol use disorder, gliosis, human, insulin/IGF
Received
13 August 2025
Accepted
28 January 2026
Copyright
© 2026 de la Monte, Tong and Sutherland. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Suzanne M de la Monte, suzanne_delamonte_md@brown.edu
Disclaimer
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