Ethanol exposure and high-fat diet: assessing the neuroimmune and metabolic mechanisms in Alzheimer's disease pathology.

Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated Tau, leading to neurofibrillary tangle formation and synaptic dysfunction. Increasing evidence indicates that these hallmark pathologies are shaped by sustained alterations in neuroimmune and metabolic homeostasis. Lifestyle-associated exposures, including ethanol consumption and high-fat diet (HFD) intake, are emerging as modulators of neuroinflammatory tone and may influence susceptibility to AD-like pathology across the lifespan. Preclinical studies show that ethanol exposure increases Aβ42/40 ratios, promotes oxidative stress, and activates Tau-associated kinases, whereas HFD induces insulin resistance, alters microglial lipid handling, and impairs Aβ clearance. These effects converge on overlapping pathways involving microglial activation, metabolic dysregulation, and kinase-phosphatase imbalance. Evidence directly examining combined ethanol and HFD exposure remains limited; however, available studies suggest co-occurring or additive effects on cognitive impairment, neuroinflammation, and synaptic dysfunction. This review synthesizes current evidence to delineate shared neuroimmune and metabolic mechanisms linking ethanol and HFD exposure to AD-related pathology. We highlight points of mechanistic overlap, including oxidative stress, inflammatory signaling, and disrupted proteostasis, while distinguishing between directly measured effects and inferred pathways. Finally, we identify key gaps in understanding how dual exposures interact and outline priorities for future studies aimed at clarifying their contribution to AD risk and progression.