Abstract
Alzheimer's disease (AD) is accompanied by alterations in retinal vascular density (VD), but the mechanisms remain unclear. This study investigated the relationship among cerebral amyloid-β (Aβ) deposition, VD, and cognitive decline. We enrolled 92 participants, including 47 AD patients and 45 healthy control (HC) participants. VD across retinal subregions was quantified using deep learning-based fundus photography, and cerebral Aβ deposition was measured with (18)F-florbetapir ((18)F-AV45) PET/MRI. Using the minimum bounding circle of the optic disc as the diameter (papilla-diameter, PD), VD (total, 0.5-1.0 PD, 1.0-1.5 PD, 1.5-2.0 PD, 2.0-2.5 PD) was calculated. Standardized uptake value ratio (SUVR) for Aβ deposition was computed for global and regional cortical areas, using the cerebellar cortex as the reference region. Cognitive performance was assessed with the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Pearson correlation, multiple linear regression, and mediation analyses were used to explore Aβ deposition, VD, and cognition. AD patients exhibited significantly lower VD in all subregions compared to HC (p < 0.05). Reduced VD correlated with higher SUVR in the global cortex and a decline in cognitive abilities (p < 0.05). Mediation analysis indicated that VD influenced MMSE and MoCA through SUVR in the global cortex, with the most pronounced effects observed in the 1.0-1.5 PD range. Retinal VD is associated with cognitive decline, a relationship primarily mediated by cerebral Aβ deposition measured via (18)F-AV45 PET. These findings highlight the potential of retinal VD as a biomarker for early detection in AD.