Ocular biomarkers for early detection and monitoring of Alzheimer's disease

Early detection of Alzheimer's disease (AD) is essential for intervention as subclinical brain changes occur well before the onset of clinical symptoms. Current imaging of amyloid plaques in the brain can detect early signs of AD but these tests are expensive and not practical for population screening. While most AD related pathology occurs in the brain, the disease has also been reported to affect vision and the eye. The retina, at the posterior of the eye, is a developmental outgrowth of the brain which is more accessible for imaging. Retinal degeneration and retinal vascular changes have previously been reported in AD using specialized techniques. AD has also been reported to influence the response of the ocular pupil to a bright flash of light, a response dependent on the cholinergic system which is impaired in AD. Research for this thesis involved collection and analysis of retinal photographs and pupil flash response parameters from participants at the McCusker Alzheimer’s Disease Research Foundation (MARF) in Perth, Australia. Data was collected from AD, mild cognitively impaired (MCI) and healthy control (HC) participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing, and from participants in the Dominantly Inherited Alzheimer Network (DIAN) study. This is the first study to investigate the retina or pupil flash response with respect to brain plaque burden, the neuropathological hallmark of AD. This approach has allowed further illumination of the connection between ocular changes and AD. It is also the first study to investigate retinal vascular changes in AD using the cost-effective and widely available retinal photography technique and hence is pertinent to the development of a population screening test for AD. The results demonstrate relationships between retinal vascular abnormalities, neocortical plaque burden and AD, and also between pupil flash response parameters, neocortical plaque burden and AD. Some ocular parameters that are found to be different in AD are also associated with elevated neocortical plaque burden in pre-clinical stages of AD, demonstrating potential as biomarkers for early, specific detection of AD. In addition, some ocular parameters were associated with longitudinal increase in neocortical plaque burden in healthy controls. These findings have been published or accepted for publication in a number of peer-reviewed journal articles. This thesis explores similarities between AD and the retinal diseases glaucoma and age-related macular degeneration and investigates signs of retinopathy in AD. Advances in research into these diseases, or pooling of research efforts, may provide novel directions for therapies and tests, and hence may have broad impact in both ophthalmology and neurology. The ocular changes reported in this thesis show potential to contribute toward a non-invasive, cost-effective screening test for pre-clinical AD and also to monitor response to treatment. An accurate, early diagnostic test for AD would enable current and future treatments to be more clinically effective, in addition to accelerating the development of new treatments. The findings of this thesis are considered relative to the existing literature.