Hepatic and Brain Spatial Gene Expression Changes in Intragastric Alcohol Fed APP/PS1 Alzheimer's Disease Mouse Model

Background Alcohol use is increasingly recognized as a significant modifier of Alzheimer's disease (AD) risk and progression. Two key organs, the liver and the brain, are central to understanding the impact of alcohol intake on AD. This is due to the liver being the primary site of alcohol detoxification and a major target of alcohol-induced injury, while the brain harbors the neuropathological hallmarks of AD. Although growing literature now links liver dysfunction to AD pathogenesis, the molecular mechanisms linking peripheral alcohol-induced liver injury to brain pathology remain poorly defined. To address this gap, we performed what is, to the best of our knowledge, the first integrated, multi-organ spatial transcriptomic analysis of liver and brain tissue from APP/PS1 AD mice subjected to chronic intragastric alcohol feeding. Methods Following five-weeks of either control- or alcohol-diet feeding of APP/PS1 mice, differentially expressed genes (DEGs) were quantified in postmortem tissue across regions of interest (ROIs) spanning periportal and perivenous liver zones, along with Aβ plaque-bearing and Aβ plaque-free regions of the cortex and hippocampus in the brain. Pathway and network analyses were then used to identify candidate hub genes and biological processes altered within and across ROIs, followed by in silico nomination of therapeutic targets and drug repurposing compounds. Results Following alcohol exposure, the most prominent transcriptional changes in the liver occurred in the perivenous zone, followed by the periportal zone. Among brain ROIs, the strongest differential expression occurred in the plaque-bearing hippocampus, with few or no DEGs detected in the remaining ROIs. These findings highlight Aβ pathology-dependent and region-selective tissue vulnerability to alcohol in the brain and liver during AD. Accordingly, cross-tissue comparisons focused on the plaque-bearing hippocampus and liver ROIs. This revealed coordinated molecular perturbations, including shared downregulation of S100a8 and Tmem267 , as well as opposing regulation of Lrp1 , Osgin1 , and Cpsf7 between the plaque-bearing hippocampus and perivenous liver ROIs, respectively. Enrichment analyses indicated convergent dysregulation of cytoplasmic processes, metal ion homeostasis, redox/oxidative stress responses, mitochondrial pathways, and immune signaling. Although no gene-level overlap was observed, identified candidate therapeutic compounds and targets converged on pathways regulating metabolic sensing, kinase and phosphatase balance, proteostasis, inflammation, autophagy, and neurovascular signaling, which are central to aging biology, chronic alcohol exposure, and AD. Conclusion These findings implicate significant liver-brain crosstalk through which chronic alcohol exposure may modulate AD-relevant pathology and reinforce the growing recognition of the liver as a critical organ in AD pathogenesis. Furthermore, these results reveal key alcohol-driven hepatic and brain gene perturbations and dysregulated pathways relevant to AD along with actionable therapeutic targets for future investigation.