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 (H(2)S), 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 H(2)S-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 H(2)S 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 H(2)S. 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. H(2)S signaling confers resilience against oxidative, inflammatory, and mitochondrial stress, whereas reduced H(2)S 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 H(2)S as an integrative driver of alcohol-related AD pathology. H(2)S signaling represents a biologically plausible convergent and modulatory pathway linking alcohol exposure to AD risk.