Chronic alcohol exposure induces amyloid-beta deposition and impaired neuronal maturation in human iPSC-derived cortical neurons and cerebral organoids.

BACKGROUND: Alcohol consumption has been associated with an increased dementia risk, including Alzheimer's disease (AD). However, the direct impact on human neuronal systems remains insufficiently characterized. METHODS: We used human induced pluripotent stem cells (iPSC)-derived cortical neurons, spheroids, and cerebral organoids exposed to physiologically relevant ethanol concentrations for seven days. We assessed neuronal maturation, dendritic morphology, and electrophysiological activity, alongside molecular and functional markers related to AD pathology. RESULTS: Chronic ethanol exposure impaired cortical neuronal maturation and network activity and reduced dendritic complexity in human iPSC-derived cortical neurons. Notably, ethanol exposure induced an amyloidogenic shift characterized by increased amyloid-beta (Aβ)-related processing. These changes were consistently observed across both 2D cortical neurons and 3D cerebral organoid models. CONCLUSION: Our findings indicate that chronic alcohol exposure disrupts neuronal maturation and promotes Alzheimer's disease-related pathology in human iPSC-derived neuronal models. This study highlights the value of human iPSC-based platforms for investigating the cellular impact of lifestyle-associated risk factors in neurodegenerative disease.