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Leveraging the retina as an accessible central nervous system (CNS) proxy, we integrated spatially resolved histopathology of retinal cross-sections with ultrastructural, proteomic, and biochemical profiling across independent postmortem cohorts spanning normal cognition, mild cognitive impairment due to AD (MCI), and AD dementia. We uncover early, progressive degeneration of excitatory glutamatergic synapses, evidenced by losses of presynaptic vesicular glutamate transporter 1 (VGLUT1) and synaptophysin, and postsynaptic density protein 95 (PSD95) and N-methyl-D-aspartate receptor subunit 2A (NMDAR2A), accompanied by disruption of synaptic ultrastructure. Retinal synaptic loss tightly associates with local accumulation of amyloid-\u03b2 42 (A\u03b242) and immature tau species, heightened oxidative stress, and upregulation of the A\u03b2-binding death receptor p75 neurotrophin receptor (p75NTR). Notably, the synapse-enriched deubiquitinase ubiquitin C-terminal hydrolase L1 (UCHL1) is profoundly dysregulated, correlates with synaptic integrity and cognition, and emerges as the strongest retinal predictor of Braak stage and cognitive status in multivariable machine-learning models. Together, these findings position retinal A\u03b2\/p75NTR-mediated UCHL1 imbalance as a proteostasis\u2013synapse mechanistic hub and candidate biomarker reflecting AD severity.<\/jats:p>","DOI":"10.64898\/2026.02.03.703406","type":"posted-content","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T06:25:25Z","timestamp":1770359125000},"source":"Crossref","is-referenced-by-count":0,"title":["Synergistic retinal UCHL1 dysregulation and synaptic vulnerability reflect Alzheimer\u2019s disease severity"],"prefix":"10.64898","author":[{"given":"Altan","family":"Rentsendorj","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Philippe","family":"Vit","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los 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