AIM: To identify the pathological role of amyloid beta (Aβ) deposition in retinal degeneration, and explore Aβ deposition on the retinal pigment epithelium cells (RPE) layer and the associated structural and functional changes in Alzheimer’s disease transgenic mice. METHODS: RPE changes in the eyes of APPswe/PS1 transgenic and none transgenic (NTG) mice over 20 months old were examined. Histological changes were investigated via hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM) examination, whereas the expression of amyloid precursor protein (APP), Aβ, Zonula occludens-1 (ZO-1) and Ionized calcium binding adaptor molecule-1 (IBA-1) were investigated using immunohistochemistry and immunofluorescence techniques. All of the obtained results were quantitatively and statistically analyzed. RESULTS: In aged transgenic mice, an APP-positive immunoreaction and Aβ deposition were detected on the RPE layer but were undetectable in NTG mice. The RPE demonstrated some vacuole changes, shortened basal infoldings and basal deposition in histopathological examination and TEM tests, wherein irregular shapes were indicated by ZO-1 disorganization through fluorescence. Furthermore, IBA-1 positive cells were observed to have accumulated and infiltrated into the RPE layer and localized beneath the RPE/Bruch’s membrane (BrM) complex, which was accompanied by an increase in BrM thickness in aged transgenic mice in comparison to NTG mice. The IBA-1 positive cells were found to be co-stained with Aβ deposition on the RPE flat mounts. CONCLUSION: The observed Aβ deposition in the RPE layer may cause RPE dysfunction, which is associated with microglia cells infiltration into the retina of aged transgenic mice, suggesting that Aβ deposition probably plays a significant role in RPE-related degenerative disease.