AIM: To investigate whether pyroptosis contributes to retinal ganglion cell (RGC) degeneration in aged TgAPPswePS1 transgenic mice and to explore the relationship between amyloid-beta (Aβ) accumulation and activation of the pyroptotic pathway in the retina. METHODS: The twelve 18-month-old TgAPPswePS1 transgenic mice and twelve 18-month-old wild-type C57BL/6J mice were used to investigate amyloid precursor protein (APP) and Aβ expression, retinal structural changes, and activation of pyroptosis in RGCs. Immunohistochemical analyses were performed to detect APP, Aβ, and pyroptosis-related proteins [NOD-like receptor thermal protein domain associated protein 3 (NLRP3), caspase-1, gasdermin D (GSDMD), interleukin (IL)-1β, and IL-18]. Quantitative assessments of retinal nerve fiber layer (RNFL) thickness were conducted to evaluate retinal integrity. RESULTS: Compared to age-matched wild-type controls, TgAPPswePS1 transgenic mice exhibited significant upregulation of APP and Aβ within RGCs. Histological analysis revealed reduced RNFL thickness, indicating structural degeneration. Notably, RGCs in transgenic mice showed robust immunoreactivity for NLRP3, caspase-1, and GSDMD, alongside elevated levels of IL-1β and IL-18, supporting the activation of pyroptosis. CONCLUSION: Aβ accumulation in RGCs is associated with retinal degeneration and activation of the pyroptosis pathway in aged TgAPPswePS1 mice. This study provides new insights into the inflammatory mechanisms underlying Aβ-related retinal neurodegeneration and suggests that targeting pyroptosis may represent a promising therapeutic strategy for retinal disorders linked to amyloid pathology.