Alterations in Retinal Signaling Across Age and Sex in 3xTg Alzheimer’s Disease Mice

BACKGROUND: Visual disturbances often precede cognitive dysfunction in patients with Alzheimer’s disease (AD) and may coincide with early accumulation of amyloid-β (Aβ) protein in the retina. These findings have inspired critical research on in vivo ophthalmic Aβ imaging for disease biomarker detection but have not fully answered mechanistic questions on how retinal pathology affects visual signaling between the eye and brain. OBJECTIVE: The goal of this study was to provide a functional and structural assessment of eye-brain communication between retinal ganglion cells (RGCs) and their primary projection target, the superior colliculus, in female and male 3xTg-AD mice across disease stages. METHODS: Retinal electrophysiology, axonal transport, and immunofluorescence were used to determine RGC projection integrity, and retinal and collicular Aβ levels were assessed with advanced protein quantitation techniques. RESULTS: 3xTg mice exhibited nuanced deficits in RGC electrical signaling, axonal transport, and synaptic integrity that exceeded normal age-related decrements in RGC function in age- and sex-matched healthy control mice. These deficits presented in sex-specific patterns among 3xTg mice, differing in the timing and severity of changes. CONCLUSION: These data support the premise that retinal Aβ is not just a benign biomarker in the eye, but may contribute to subtle, nuanced visual processing deficits. Such disruptions might enhance the biomarker potential of ocular amyloid and differentiate patients with incipient AD from patients experiencing normal age-related decrements in visual function.