Imaging Soluble Amyloid Oligomer Flow Dynamics in the Eyes for Detection of Alzheimer's Disease

This application addresses the overarching challenge of the early detection of Alzheimer’s disease (AD). It does so by proposing a novel approach to image soluble Abeta oligomer (SAbO) clearance dynamics. SAbOs occur years earlier before amyloid-b (Abeta) plaques and are thought to be the real culprits behind neurodegeneration. Importantly, this project focuses on detecting SAbO in the retina by using signals emitted from an innovative fluorescent nanobody developed by this team. The pathology of AD is characterized by the initial presence of extracellular deposits of misfolded and aggregated Abeta proteins, which subsequently spread from the hippocampus to the cerebral cortex causing neuronal death and, ultimately, loss of memory and cognition, and the ability to speak. At present, no disease- modifying therapy is effective against AD, nor is it possible to diagnose the disease’s early onset or progress. Recent findings indicate that elevated levels of Abeta proteins in brain and eyes are associated with dysfunctional neuronal network. Because AD undergoes a protracted asymptomatic stage before it reaches advanced conditions, a window of opportunity exists for early intervention. Successful detection of the onset of this disease via routine screening will improve therapeutic outcomes and save lives. The retina is part of the CNS and is densely covered with capillaries and other blood vessels. For these reasons it is possible to observe SAbO clearance in blood within the retina. We present a novel SAbO clearance process that can be visualized in the retina using a fluorescein-labeled, SAbO-specific nanobody. Because SAbO forms early in AD, we propose eventual development of retina screening as part of eye exams. In collaboration with Prof. Joanne Matsubara, using our newly developed fluorescein-labeled nanobody, we discovered a dynamic SAbO clearance process in the retina of healthy human donor eyes. In retinas, we observe SAbO with the size and shape with the dimension of nanoparticles within the blood capillary vessels of the inner limiting membrane. In contrast, we noted that this SAbO clearance process is disrupted significantly in AD human donor eyes. Based on this observation, we hypothesize that disruption of SAbO clearance could promote Abeta aggregation. These data corroborate with our recent report showing significant Abeta deposits in AD compared to control human donor eyes. Based on these results, we propose, that dysregulated SAbO clearance mechanisms results in reduced clearance of SAbO nanoparticles, and subsequent enhanced Abeta deposits in the retina. We propose to capitalize on these observable changes in SAbO dynamics as a biomarker for early AD detection. In this project, our objectives are to (i) optimize the development of a fluorescent nanobody, and (ii) evaluate early dysfunctional clearance of SAbO nanoparticles as an early biomarker of AD. Project Number: 1R01AG098771-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Wellington Pham | Institution: VANDERBILT UNIVERSITY MEDICAL CENTER, NASHVILLE, TN | Award Amount: $659,026 | Activity Code: R01 | Study Section: Imaging Probes and Contrast Agents Study Section[IPCA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11296483