Reactive Oxygen Species as a Common Pathological Link Between Alcohol Use Disorder and Alzheimer's Disease with Therapeutic Implications

Abstract

Chronic alcohol consumption leads to excessive production of reactive oxygen species (ROS), driving oxidative stress that contributes to both alcohol use disorder (AUD) and Alzheimer's disease (AD). This review explores how ROS-mediated mitochondrial dysfunction and neuroinflammation serve as shared pathological mechanisms linking these conditions. We highlight the role of alcohol-induced oxidative damage in exacerbating neurodegeneration and compare ROS-related pathways in AUD and AD. Finally, we discuss emerging therapeutic strategies, including mitochondrial antioxidants and inflammasome inhibitors, that target oxidative stress to mitigate neurodegeneration. Understanding these overlapping mechanisms may provide new insights for preventing and treating ROS-driven neurodegenerative disorders.

Keywords: Alzheimer’s disease (AD); alcohol use disorder (AUD); reactive oxygen species (ROS).

Figure 1

Oxidative stress as a central mechanism linking AUD and AD. The schematic illustrates how oxidative stress and mitochondrial dysfunction contribute to neuroinflammation and neuronal damage in AUD and AD. On the left side, alcohol consumption disrupts the gut barrier, increasing intestinal permeability and allowing for LPS to enter the bloodstream. LPS activates TLR4, triggering NLRP3 inflammasome assembly and promoting the release of pro-inflammatory cytokines and microRNAs(miRNAs). Alcohol-induced mitochondrial damage leads to ATP depletion, mitochondrial DNA (mtDNA) release, and oxidative stress, amplifying neuroinflammation. Chronic alcohol exposure also activates the MEOS in brain tissues, where CYP2E1 catalyzes ethanol metabolism, producing excessive ROS and acetaldehyde, which contributes to unfolded protein response (UPR) and neuronal toxicity. On the right side, Aβ and tau protein accumulation, key hallmarks of AD, activate TLR4 signaling in microglia, leading to NLRP3 inflammasome assembly and inflammatory responses. The interaction between Aβ and ABAD increases ROS accumulation and mitochondrial dysfunction by inactivating ABAD, which usually exists in an active tetramer form. Inflammatory responses in both AUD and AD create a vicious cycle of ROS production and mitochondrial dysfunction, reinforcing oxidative damage through a bidirectional feedback mechanism. Mitochondrial impairment leads to ETC disruption, ATP depletion, and mPTP activation, increasing oxidative stress. As the cycle progresses, neuronal cell death through pyroptosis, brain structural changes, and Alzheimer’s pathology progression accelerate. The entorhinal cortex, known as one of the earliest sites of degeneration in AD, exhibits pathological changes, such as nerve fiber tangling and cell death [14,15,16,17,18].

Figure 2

Therapeutic strategies targeting ROS in AUD and AD. The interplay between the gut–brain axis, mitochondrial dysfunction, and neuroinflammation highlights potential therapeutic targets in AD and AUD. In the gut, probiotics and prebiotics help maintain intestinal integrity, regulate the gut microbiota, and prevent LPS translocation. Increased intestinal permeability allows for LPS to enter the bloodstream, activating TLR4 and triggering NLRP3 inflammasome activation, which leads to BBB dysfunction. At the mitochondrial level, MitoQ reduces ROS by targeting the inner mitochondrial membrane, preventing lipid peroxidation and ROS production at Complexes I and III. SS-31 binds to cardiolipin to stabilize mitochondrial dynamics, prevent mPTP formation, and modulate Dynamin-related protein 1 (DRP1). Both compounds inhibit NLRP3 inflammasome activation, thereby mitigating neuroinflammation. Inflammasome inhibitors provide additional therapeutic strategies. MCC950 blocks NEK7/NLRP3 interaction by binding the Walker B motif in the NACHT domain, suppressing caspase-1 activation and downstream inflammation. SB_NI_112 inhibits NF-κB signaling to reduce NLRP3 activation and the production of inflammatory cytokines. VX-765 selectively inhibits caspase-1, preventing IL-1β release and attenuating neuroinflammation.