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

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 <i>convergent and modulatory</i> pathway linking alcohol exposure to AD risk.