Retinal Proteome Changes Mirror Brain Pathology and Reveal Synaptic and Cytoskeletal Dysfunction in Alzheimer's

Visual dysfunction is increasingly recognized as an early feature of Alzheimer's disease (AD), yet the molecular mechanisms underlying retinal neurodegeneration and their relationship to cerebral pathology remain unclear. Here, we performed comprehensive mass spectrometry-based proteomics on paired retinal and hippocampal tissue from the same postmortem donors (8 AD, 8 non-demented controls) to identify disease-associated molecular signatures and assess their overlap between these tissues. Using a sequential dual-extraction protocol, we identified 370 differentially abundant retinal proteins in AD, including established APP-processing regulators (SORL1, APMAP) and synaptic proteins. Retinal proteomes clearly separated AD from control cases in principal component analysis. Notably, 87% of proteins were detected in both retina and hippocampus, with 68 differentially abundant proteins shared between tissues. Many retinal proteins correlated with neuropathological stages of disease, and four proteins (APMAP, CD109, NRXN1, PACSIN3) showed particularly strong retina-brain correlations. Functional enrichment analysis revealed convergent alterations in synaptic organization, cytoskeletal dynamics, mitochondrial function, cell adhesion, and APP metabolism in both tissues. Cell-type mapping using single-cell retinal reference data indicated that most proteomic changes were broadly distributed across cell types, though some showed enrichment in microglia or photoreceptors. These findings demonstrate that the AD retina undergoes substantial molecular alterations that mirror brain pathology. The identified molecular changes provide mechanistic insights into visual dysfunction in AD and support the retina as an accessible window for assessing brain pathology, with retinal proteins correlated with cerebral pathology representing promising candidates for non-invasive biomarker development.