Multimodal Retinal Imaging Correlates With Brain Atrophy and Plasma Biomarkers in Alzheimer's Disease

Purpose: To investigate retinal structural and microvascular changes in Alzheimer's disease (AD) and evaluate their associations with neuroimaging markers, plasma biomarkers, and cognitive impairment. Methods: This cross-sectional study included 181 participants (95 with AD and 86 cognitively unimpaired controls). AD diagnosis was established according to National Institute on Aging-Alzheimer's Association criteria with positive amyloid-β positron emission tomography imaging. Retinal structure and microvasculature were assessed using swept-source optical coherence tomography (OCT) and OCT angiography (OCTA). Cortical thickness and gray matter volume were quantified using structural magnetic resonance imaging. Plasma Aβ42 and phosphorylated tau-217 (p-tau217) were measured, and cognitive function was evaluated using the Mini-Mental State Examination and Montreal Cognitive Assessment (MoCA). Results: Compared with controls, patients with AD demonstrated reduced retinal nerve fiber layer, ganglion cell-inner plexiform layer (GCIPL), inner nuclear layer, and outer retinal layer thicknesses, together with lower superficial vascular complex (SVC) and deep vascular complex densities (all P < 0.001). GCIPL thickness and SVC density were associated with cortical atrophy in AD-vulnerable regions, including temporal, parietal, and occipital cortices. Lower plasma Aβ42 levels were associated with reduced retinal layer thickness and vascular density, whereas higher p-tau217 levels were associated with reduced outer retinal layer thickness and SVC density. GCIPL thickness showed the strongest association with cognitive performance, while lower SVC density was associated with poorer MoCA scores. APOE ε4 carriers exhibited greater GCIPL thinning, reduced retinal vascular density, and more extensive cortical abnormalities despite similar plasma Aβ42 and p-tau217 levels. Conclusions: Retinal neuronal and microvascular alterations are associated with AD-related molecular pathology, cerebral neurodegeneration, APOE ε4-related vulnerability, and cognitive impairment. OCT/OCTA may provide a noninvasive adjunct approach for characterizing neurodegenerative and neurovascular changes in AD. Translational Relevance: Retinal imaging may provide a scalable and noninvasive approach for detecting and monitoring AD pathology.