Ocular indicators of Alzheimer's: exploring disease in the retina

Abstract

Although historically perceived as a disorder confined to the brain, our understanding of Alzheimer's disease (AD) has expanded to include extra-cerebral manifestation, with mounting evidence of abnormalities in the eye. Among ocular tissues, the retina, a developmental outgrowth of the brain, is marked by an array of pathologies in patients suffering from AD, including nerve fiber layer thinning, degeneration of retinal ganglion cells, and changes to vascular parameters. While the hallmark pathological signs of AD, amyloid β-protein (Aβ) plaques and neurofibrillary tangles (NFT) comprising hyperphosphorylated tau (pTau) protein, have long been described in the brain, identification of these characteristic biomarkers in the retina has only recently been reported. In particular, Aβ deposits were discovered in post-mortem retinas of advanced and early stage cases of AD, in stark contrast to non-AD controls. Subsequent studies have reported elevated Aβ_42/40 peptides, morphologically diverse Aβ plaques, and pTau in the retina. In line with the above findings, animal model studies have reported retinal Aβ deposits and tauopathy, often correlated with local inflammation, retinal ganglion cell degeneration, and functional deficits. This review highlights the converging evidence that AD manifests in the eye, especially in the retina, which can be imaged directly and non-invasively. Visual dysfunction in AD patients, traditionally attributed to well-documented cerebral pathology, can now be reexamined as a direct outcome of retinal abnormalities. As we continue to study the disease in the brain, the emerging field of ocular AD warrants further investigation of how the retina may faithfully reflect the neurological disease. Indeed, detection of retinal AD pathology, particularly the early presenting amyloid biomarkers, using advanced high-resolution imaging techniques may allow large-scale screening and monitoring of at-risk populations.

Keywords: Alzheimer’s disease; Amyloid-beta; Neurodegenerative disease; Ocular abnormalities; Retinal biomarkers; Tauopathy.

Fig. 1

Flat-mount retinas from AD patients exhibit the accumulation of Aβ deposits. a–c Representative microscopic images from a definite AD patient (74 years) and a matched control individual (CTRL; 71 years) stained with anti-Aβ₄₂ C-terminal-specific antibody (12F4) and visualized with peroxidase-based labeling (DAB). Blood vessel structures seen as lighter lanes. c Classical mature Aβ plaques observed along a retinal blood vessel. d, e Fluoresence labeling of Aβ₄₂-containing deposits detected in retina of AD patient (yellow), using curcumin (green), 12F4 antibody (red), and DAPI nuclear staining (blue). Sudan Black B (SBB) is used to quench non-specific autofluorescent signal. f Compact extracellular Aβ plaque and cytosolic Aβ₄₀ accumulations observed following curcumin and anti-Aβ₄₀ C-terminal-specific antibody (11A5-B10) staining in post-mortem retinas of AD patients. Arrows indicate various types of Aβ plaques Images a-c adopted from La Morgia et al., Annals of Neurology, vol. 79, no. 1, pp. 90–109, 2015

Fig. 2

Manifestations of AD in the Human Retina. a Visual pathway. b Eye-sagittal plane. c Retinal flat-mount shows the geometric distribution of pathology by quadrant with more consistent findings of NFL thinning indicated by darker shading. d Cross section of retina and adjacent ocular tissues shows the distribution of pathology by tissue layer. Aβ amyloid beta-protein, pTau phosphorylated tau, NFL nerve fiber layer, GCL ganglion cell layer, IPL inner plexiform layer, INL inner nuclear layer, OPL outer plexiform layer, ONL outer nuclear layer, ILM inner limiting membrane, OLM outer limiting membrane, IS/OS inner and outer segments of photoreceptor layer, RPE retinal pigment epithelium, P. Pole posterior pole