# Alcohol-Induced Dysregulation of Hydrogen Sulfide Signaling in Alzheimer’s Disease—Narrative Mechanistic Synthesis Review

## TL;DR

This review explores how alcohol affects hydrogen sulfide signaling, a pathway linked to Alzheimer's disease, suggesting alcohol may worsen cognitive decline through non-traditional mechanisms.

## Contribution

The paper proposes hydrogen sulfide signaling as a modulatory pathway linking alcohol exposure to Alzheimer's disease risk.

## Key findings

- Alcohol exposure is associated with oxidative stress, neuroinflammation, and vascular dysfunction, which overlap with hydrogen sulfide-regulated processes.
- Reduced hydrogen sulfide bioavailability increases neuronal vulnerability and cognitive impairment.
- Alcohol-related cognitive decline often occurs without classical Alzheimer's pathology, indicating non-canonical mechanisms.

## Abstract

Alcohol use disorder (AUD) is highly comorbid with psychiatric conditions and is increasingly recognized as a modifiable factor associated with cognitive decline and dementia, including Alzheimer’s disease (AD). While epidemiological and experimental studies consistently demonstrate that chronic alcohol exposure exacerbates neurodegenerative vulnerability rather than implying a single dominant causal pathway, accumulating evidence supports a multifactorial and context-dependent framework in which alcohol acts as a disease-modifying stressor that perturbs endogenous adaptive and resilience mechanisms. Hydrogen sulfide (H2S), involved in redox regulation, mitochondrial function, neuroinflammatory control, and vascular homeostasis, has emerged as a candidate pathway that may be indirectly affected by alcohol exposure and relevant to neurodegenerative processes. This narrative mechanistic review synthesizes preclinical and clinical data examining alcohol-induced perturbations and H2S-related signaling pathways in the context of AD. We analyzed studies on the effects of acute and chronic alcohol exposure, as well as on cellular processes influenced by H2S bioavailability and signaling. Across experimental models and human studies, alcohol exposure was consistently associated with oxidative and mitochondrial stress, neuroinflammation, and vascular dysfunction—processes that overlap with biological domains normally regulated by H2S. Alcohol-related cognitive impairment frequently occurs in the absence of proportional increases in classical AD pathology, suggesting that alcohol may accelerate disease progression through non-canonical mechanisms. H2S signaling confers resilience against oxidative, inflammatory, and mitochondrial stress, whereas reduced H2S bioavailability or disrupted sulfide-dependent signaling increases neuronal vulnerability and cognitive impairment. However, the available data do not support a unidirectional or exclusive role for H2S as an integrative driver of alcohol-related AD pathology. H2S signaling represents a biologically plausible convergent and modulatory pathway linking alcohol exposure to AD risk.