Advisor(s)

Edmund Arthur

Committee Member(s)

Erik Roberson
Juan Piantino
Keith McGregor
Kristina Visscher
Lawrence Sincich

Document Type

Dissertation

Date of Award

1-27-2026

Degree Name

Doctor of Philosophy (PhD)

School

School of Optometry

Department

Optometry

Abstract

Alzheimer’s disease is a progressive neurodegenerative disorder that causes damage to the neurons that are present in the brain. Progress in the management and treatment of AD is limited by lack of early diagnostics, which are critical to the development of effective therapies. It is therefore critical to develop non-invasive/cost efficient biomarkers to aid in early diagnosis and interventions to prevent or delay dementia onset. While Positron Emission Tomography (PET) and cerebrospinal fluid assessment have greatest utility, they are not routinely used because they are expensive and invasive, respectively. Retinal imaging offers a promising, low-cost, and non-invasive avenue for detecting early AD risk, owing to shared embryologic, anatomic, and physiological features between the retina and brain. The goal of this thesis was to develop two novel retinal biomarkers for early AD detection and disease monitoring: (1) mid-peripheral capillary free zones (CFZs, also termed retinal perivascular spaces), which may reflect brain perivascular space health, and (2) putative retinal gliosis, which may serve as an in vivo marker of neuroinflammation. These were assessed using imaging modalities including spectral-domain OCT (SD-OCT), en face OCT, and OCT angiography (OCTA). Additionally, we examined the association between retinal vascular changes (including mid-peripheral CFZs) and brain perivascular space metrics and explored the relationship of retinal gliosis with plasma biomarkers. Our findings demonstrated that cognitively unimpaired older adults at high genetic risk for AD (APOE ε4 carriers with a positive family history) exhibited significantly larger periarteriole and perivenule CFZs compared with low-risk individuals. Cognitively unimpaired participants who were amyloid beta (Aβ) PET+ (preclinical AD) showed significantly greater putative retinal gliosis surface area compared with those who were Aβ PET– (controls). Although mid-peripheral CFZs showed a positive trend with MRI-visible enlarged perivascular space (ePVS) maximum width, this association did not reach significance. However, vessel density was significantly associated with ePVS minimum length, and foveal avascular zone (FAZ) size/effective diameter was significantly associated with ePVS median volume and width. Retinal gliosis correlated significantly with plasma p-tau217 (β = 0.43–0.48, p ≤ 0.022) but not with Aβ42/Aβ40, NfL, or p-tau181. Finally, integration of retinal imaging biomarkers such as gliosis with blood-based biomarkers demonstrated high diagnostic sensitivity and specificity. These findings support the potential of retinal biomarkers as a robust, accessible, and scalable framework for early AD risk detection and multimodal preclinical AD screening.

ProQuest Publication Number

32282346

ISBN

9798273349742

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