Retinal dysfunction in APOE4 knock‐in mouse model of Alzheimer's disease

Abstract INTRODUCTION Late‐onset Alzheimer's Disease (LOAD) is the predominant form of Alzheimer's disease (AD), and apolipoprotein E ( APOE ) ε4 is a strong genetic risk factor for LOAD. As an integral part of the central nervous system, the retina displays a variety of abnormalities in LOAD. Our study is focused on age‐dependent retinal impairments in humanized APOE4 ‐knock‐in (KI) and APOE3 ‐KI mice developed by the Model Organism Development and Evaluation for Late‐Onset Alzheimer's Disease (MODEL‐AD) consortium. METHODS All the experiments were performed on 52‐ to 57‐week‐old mice. The retina was assessed by optical coherence tomography, fundoscopy, fluorescein angiography, electroretinography, optomotor response, gliosis, and neuroinflammation. mRNA sequencing was performed to find molecular pathways. RESULTS APOE4 ‐KI mice showed impaired retinal structure, vasculature, function, vision, increased gliosis and neuroinflammation, and downregulation of synaptogenesis. DISCUSSION The APOE ε4 allele is associated with increased susceptibility to retinal degeneration compared to the APOE ε3 allele. Highlights Apolipoprotein E (APOE) 4 mice exhibit structural and functional deficits of the retina. The retinal defects in APOE4 mice are attributed to increased neuroinflammation. APOE4 mice show a unique retinal transcriptome, yet with key brain similarities. The retina offers a non‐invasive biomarker for the detection and monitoring of Alzheimer's disease.