Abhyankar, Surabhi D.Luo, QianyiHartman, Gabriella D.Mahajan, NehaCorson, Timothy W.Oblak, Adrian L.Lamb, Bruce T.Bhatwadekar, Ashay D.2025-03-242025-03-242025Abhyankar SD, Luo Q, Hartman GD, et al. Retinal dysfunction in APOE4 knock-in mouse model of Alzheimer's disease. Alzheimers Dement. 2025;21(2):e14433. doi:10.1002/alz.14433https://hdl.handle.net/1805/46485Introduction: 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.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalApolipoprotein E (APOE)Late‐onset Alzheimer's diseaseBiomarkerRetinaRetinal dysfunctionArticle