Retinal tau imaging and histopathology as emerging Alzheimer's disease biomarkers: A systematic review.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition and tau protein aggregation. The retina, as an extension of the central nervous system, has emerged as a promising site for detecting biomarkers of AD. Objective: This systematic review synthesizes the current evidence on retinal tau protein as a diagnostic tool for AD and related tauopathies. Methods: This systematic review adhered to PRISMA guidelines, analyzing studies on retinal tau biomarkers, structural changes, and diagnostic imaging techniques. The included studies encompassed molecular investigations, experimental models, and clinical imaging approaches. Results: Retinal phosphorylated tau (p-tau) and related isoforms were consistently identified as correlating with systemic AD pathology, including Braak staging. Experimental and clinical studies revealed early retinal changes, such as ganglion cell degeneration and blood-retina barrier breakdown, that preceded cognitive decline. Diagnostic advancements, including curcumin fluorescence imaging, ferritin nanocages, and hyperspectral imaging, demonstrated enhanced precision and feasibility for detecting retinal tau and Aβ in vivo and postmortem. These findings suggest that retinal tau serves as a robust biomarker for AD. Conclusions: Retinal tau pathology represents a powerful diagnostic tool, providing non-invasive access to early AD pathology. By integrating molecular insights with advanced imaging modalities, retinal biomarkers could enable earlier diagnosis, therapeutic monitoring, and personalized treatment strategies. Future research should focus on longitudinal validation of retinal biomarkers across diverse populations.