Background: Alzheimer’s disease (AD), the seventh leading cause of death in the United States, is characterized by progressive cognitive decline and neurodegeneration. Although traditionally considered a CNS-restricted disorder, mounting evidence suggests that peripheral organs, particularly the gastrointestinal (GI) tract, shape disease risk. Gut microbiota composition, intestinal inflammation, and microbially derived metabolites influence brain function and may contribute to early susceptibility to neurodegenerative disease. Dietary patterns, especially high-fat diets, further exacerbate systemic inflammation, metabolic dysfunction, and amyloid-β and tau pathology. While the intestine has been explored in this context, the stomach remains largely overlooked despite its direct neural connection to the brain via the vagus nerve. Gastric epithelial injury triggers gastric metaplasia, a reparative response marked by parietal cell loss. Because gastric metaplasia is tightly linked to inflammation, and inflammation is increasingly implicated in AD pathogenesis, the stomach may represent an underappreciated site of peripheral AD-related pathology. Whether high-fat diets and AD susceptibility interact to alter gastric remodeling or induce neurodegenerative markers is unknown. We hypothesized that a high-fat diet induces gastric epithelial injury which, in the presence of AD risk genes, amplifies inflammation and accelerates neurodegenerative processes. Methods: Adult APP/PS1 transgenic mice, a well-characterized AD model, were fed either standard chow or a high-fat diet (54% kcal from fat) for 12 weeks. Gastric tissue was collected for histological and immunofluorescent analyses, and gastric contents were harvested for microbial profiling. Immunostaining was performed for markers of gastric metaplasia (CD44v9, AQP5), parietal cells (H + /K + -ATPase), tuft cells (DCLK1), immune infiltrates, and phosphorylated tau (p-tau), a key AD-associated protein. Results: High-fat diet-fed APP/PS1 mice exhibited pronounced gastric epithelial remodeling compared to chow-fed controls, including extensive spasmolytic polypeptide-expressing metaplasia (SPEM), parietal cell loss, and emergence of metaplastic lineages marked by elevated CD44v9 and AQP5. DCLK1 + tuft cells and type 2 inflammatory populations- mast cells, macrophages, and ILC2s- were markedly expanded. Notably, gastric tissues from high-fat diet-fed APP/PS1 mice displayed increased p-tau localized within the gastric stroma, demonstrating that AD-associated molecular signatures can arise in peripheral tissues under combined genetic and dietary stress. 16S rRNA sequencing revealed expansion of pathobionts that may contribute to gastric injury and remodeling. Conclusions: High-fat diet consumption in the context of AD susceptibility drives substantial gastric remodeling- metaplasia, parietal cell atrophy, tuft cell expansion, and inflammation- accompanied by elevated neurodegenerative protein markers. These findings identify a previously unrecognized link between diet, gastric epithelial biology, and AD-related pathology, suggesting that the stomach may represent an important peripheral contributor to neurodegenerative disease. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Grozis et al. (2026) studied this question.