Novel Retinal Biomarker Development in Early Alzheimer's Disease

1 Alzheimer’s disease (AD) is a progressive neurodegenerative disease affecting approximately 6.7 million 2 Americans aged 65 and older and projected to reach 13.8 million by 2060. Progress in the management and 3 treatment of AD is limited by lack of early diagnostics, which are critical to the development of effective 4 therapies. AD is currently described in three stages: preclinical, mild cognitive impairment (MCI), and 5 Alzheimer’s dementia. The difficulty lies in detecting the disease during the preclinical phase, when patients 6 show no clinical symptoms of cognitive impairment but there is underlying pathology. Currently, we are limited 7 to detecting the accumulation of amyloid plaques in the brain using expensive and invasive methods such as 8 Positron Emission Tomography and cerebrospinal fluid assessment via lumbar puncture. The goal of the 9 proposal is to quantify and validate two novel retinal biomarkers for early AD detection and monitoring of 10 disease progression known as the retinal mid-peripheral capillary free zones (CFZs) and putative retinal 11 gliosis. As an extension of the brain, the retina provides a potential non-invasive window for early detection of 12 AD. Our group has recently characterized and quantified a novel retinal vascular biomarker for early AD 13 detection known as the retinal mid-peripheral CFZs (periarteriole and perivenule CFZs) using Optical 14 Coherence Tomography Angiography (OCTA). We have also recently shown larger surface area of putative 15 retinal gliosis in preclinical AD patients compared to controls in vivo using en face Spectral Domain OCT (SD- 16 OCT), suggesting putative retinal gliosis as a novel biomarker of AD-related neuroinflammation in the retina. 17 Building on these prior results, our central hypothesis is that these two novel retinal biomarkers will change 18 over time and will be associated with changes in plasma ptau217, and perivascular space burden on magnetic 19 resonance imaging (MRI) in early AD. We will test our central hypothesis by completing the following aims: 20 AIM 1: Determine if the retinal mid-peripheral CFZs change with disease progression and predict 21 changes in MRI perivascular spaces in the centrum semiovale in cognitively unimpaired (CU) older 22 adults at high-risk for AD. We will collect baseline and longitudinal OCTA and MRI data in high- and low-risk 23 CU older adults. AIM 2A: Determine if the surface area of putative retinal gliosis changes with disease 24 progression and predicts changes in plasma ptau217 in preclinical AD. We will collect baseline and 25 longitudinal en face SD-OCT and plasma data in preclinical AD patients and controls. AIM 2B: Compare the 26 diagnostic utility of putative retinal gliosis to plasma inflammatory panel to distinguish between 27 preclinical AD and controls. We will use baseline putative retinal gliosis, plasma GFAP, and proinflammatory 28 cytokine data to develop an ROC curve and classification comparison plots to distinguish between preclinical 29 AD and controls. This project will provide novel information about the association between changes in retinal, 30 MRI, and plasma biomarkers for early AD detection, and monitoring of disease progression. Project Number: 1R56AG096140-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Edmund Arthur | Institution: UNIVERSITY OF ALABAMA AT BIRMINGHAM, BIRMINGHAM, AL | Award Amount: $405,955 | Activity Code: R56 | Study Section: Aging Systems and Geriatrics Study Section[ASG] View on NIH RePORTER: https://reporter.nih.gov/project-details/11528290