Beta-amyloid sequelae in the eye: a critical review on its diagnostic significance and clinical relevance in Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. There is no test for its definitive diagnosis in routine clinical practice. Although phase III clinical trials have failed, only symptomatic treatment is currently available; a possible reason for these failed trials is that intervention commenced at an advanced stage of the disease. The hallmarks of an AD brain include plaques comprising of extracellular beta-amyloid (Aβ) protein aggregates and intracellular hyperphosphorylated neurofibrillary tangles of tau. Research into the preclinical diagnosis of AD has provided considerable evidence regarding early neuropathological changes using brain Aβ imaging and the cerebrospinal fluid biomarkers, Aβ and tau. Both these approaches have limitations that are expensive, invasive or time consuming and thus preclude them from screening at-risk population. Recent studies have demonstrated the presence of Aβ plaques in the eyes of AD subjects, which is positively associated with their brain Aβ burden. Thus ocular biomarkers point to a potential avenue for an earlier, relatively low-cost diagnosis in order for therapeutic interventions to be effective. Here we review the literature that spans the investigation for the presence of Aβ in aging eyes and the significance of its deposition in relation to AD pathology. We discuss clinical studies investigating in vivo imaging of Aβ in the eye and its association with brain Aβ burden and therapies that target ocular Aβ. Finally, we focus on the need to characterize AD-specific retinal Aβ to differentiate Aβ found in some eye diseases. Based on the current evidence, we conclude that integration of ocular biomarkers that can correctly predict brain Aβ burden would have an important role as a non-invasive, yet economical surrogate marker in the diagnostic process of AD.

Retinal Ganglion Cells and Circadian Rhythms in Alzheimer’s Disease, Parkinson’s Disease, and Beyond

“…The presence of neuropathological hallmarks, i.e., β-amyloid plaques (30, 107, 108), α-synuclein (51, 52), and huntingtin (98) in the retina of these neurodegenerative disorders demonstrates that the retina is specifically affected by neurodegeneration and affords access to potential biomarkers of the disease.…”

Prion protein modulates iron transport in the anterior segment: Implications for ocular iron homeostasis and prion transmission

“…This is an important unanswered question with significant clinical implications since a breach of these monolayers is likely to result in corneal and lens opacities with eventual blindness. Soluble PrP C in the aqueous and vitreous humor is probably released from lining cells, and is likely to play a protective role by binding amyloid-β, a proteolytic product of amyloid precursor protein implicated in the pathogenesis of glaucoma and age related macular degeneration (Anderson et al, 2004; Guillot-Sestier et al, 2009; Prakasam et al, 2010; Ratnayaka et al, 2015; Salazar et al, 2017; Shah et al, 2017). Further investigations are necessary to understand the functional significance of soluble PrP C , and strategies to use this information in delaying or preventing ocular disorders associated with increased levels of amyloid-β.…”

Vascular retinal biomarkers improves the detection of the likely cerebral amyloid status from hyperspectral retinal images

“…The retina is an extension of the central nervous system (CNS) and represents the only part of the CNS which is noninvasively accessible for imaging by optical means. The eye therefore has been therefore suggested as a window to the brain offering a unique site to measure biomarkers for neurodegenerative diseases [8,9].…”