Retinal manifestations and their diagnostic significance in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative condition manifesting as cognitive decline, memory deterioration, and behavioral alterations. Late-onset AD accounts for most diagnosed cases, with the onset of symptoms usually occurring after 65 years. At present, there are no proven treatments that alter the course of AD. For early detection and intervention, it is crucial to understand the underlying mechanisms and identify promising biomarkers for AD. Research suggests that the pathological processes of AD initiate years before the emergence of noticeable symptoms, which makes the early diagnosis more challenging. While various biomarkers, such as cognitive tests, imaging, and biological markers in blood and cerebrospinal fluid, have been proposed for early detection, their reliability, as matched with symptomatic stages, varies significantly. As a component of the central nervous system, the retina has attracted attention as a potential site for studying AD-related changes. Studies from human and animal models have revealed structural, vascular, functional, and metabolic changes in the retina through the early phases of AD. Furthermore, advances in ophthalmic technologies have facilitated the identification and characterization of AD-related changes such as amyloid-β and tau-protein deposition. This review provides an overview and perspective on AD as they relate to the retina and highlights the importance of ocular changes as surrogates for understanding and diagnosing AD.

Keywords: Alzheimer's disease; amyloid-β; neurodegeneration; non-invasive biomarkers; ocular imaging; retina; retina-brain axis; retinal biomarkers; retinal pathology; tau pathology.

Figure 1.

Summary of retinal abnormalities in Alzheimer's disease (AD). Left: Normal retinal structure and cell types. Right: Pathological changes in the retina associated with AD. Reduced nerve fiber layer thickness has been reported in AD, alongside death of retinal ganglion cells (RGCs). Amyloid-β (Aβ) deposition is observed around the RGCs and around retinal blood vessels, and Aβ plaques are apparent. There is a loss of blood vessel density in AD, alongside reduced arterial diameter. Blood-retinal barrier breakdown increases inflammation in the retina. Increased numbers of activated microglia are observed in AD patients, and Müller cell gliosis is reported in animal models of AD. (Created with BioRender.com)

Figure 2.

Diagrammatic representation highlighting various methods for detecting, monitoring, and diagnosing Alzheimer's disease (AD) changes using the visual system. Functioning as an extension of the central nervous system, the retina has emerged as a promising domain for investigating AD-related changes and uncovering potential biomarkers. LGN: lateral geniculate nucleus; OCT: optical coherence tomography; OCTA: optical coherence tomography angiography; HIS: hyperspectral imaging; FLIO: Fluorescence Lifetime Imaging Ophthalmoscopy; SLO: scanning laser ophthalmoscopy. (Created with BioRender.com).