Early Retinal UCHL1 Dysregulation Coupled With Synaptic Loss Reflects Alzheimer's Disease Severity

Synaptic dysfunction is a major driver of cognitive decline in Alzheimer's disease (AD), yet its extent and molecular basis in the retina remain poorly defined. We integrated postmortem retinal and matched brain histopathology with ultrastructural, proteomic, biochemical, and machine-learning analyses across cognitively normal, mild cognitive impairment, and AD cohorts. Retinal glutamatergic synapses exhibited early, progressive degeneration, marked by loss of presynaptic vesicular glutamate transporter 1 (VGLUT1) and synaptophysin and postsynaptic density protein 95 (PSD95) and N-methyl-D-aspartate receptor subunit 2A (NMDAR2A), along with ribbon synapse ultrastructural disruption. Synaptic deficits correlated with amyloid-β₄₂ (Aβ₄₂), pathogenic tau, oxidative stress, the Aβ-binding p75 neurotrophin receptor, and glial activation that paralleled disease progression. Proteomics revealed widespread synaptic remodeling accompanied by disease-associated microglia, astrocyte-mediated excitotoxicity, and pyroptotic pathways. The synapse-enriched deubiquitinase ubiquitin C-terminal hydrolase L1 (UCHL1) was dysregulated early, particularly in horizontal and bipolar interneurons, and strongly associated with synaptic loss and neuroinflammation. Mechanistically, fibrillar Aβ₄₂ induced rapid UCHL1 and synaptic depletion in human and murine neurons before overt neurodegeneration. Machine-learning models identified retinal UCHL1 as the strongest predictor of Braak stage and cognitive impairment. These findings establish the retina as an early site of AD synaptopathy and position UCHL1 as a candidate biomarker and mechanistic mediator linking amyloid pathology, neuroinflammation, and synaptic vulnerability.