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 Aβ42/40 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.

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

“…In line with the above findings, numerous studies examining the retinas of sporadic and transgenic animal models of AD have reported Aβ deposits, vascular Aβ, pTau, and paired helical filament-tau (PHF-tau), often in association with RGC degeneration, local inflammation (i.e., microglial activation), and impairments of retinal structure and function (11,39,40,42,(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61). These studies, which included a variety of transgenic rat and mouse models, as well as the sporadic rodent model of AD, Octodon degus, demonstrated abundant Aβ deposits, mainly in the innermost retinal layers (RGCs and NFL) (40,42,45,49,52,54,57).…”

“…A couple of studies that were unable to detect Aβ in the human AD retina analyzed horizontal cross sections spanning a narrow strip from the nasal to temporal quadrants (41,43), rather than screening large regions in flat mounts, thus limiting their analysis to regions that are largely spared of amyloid pathology in AD patients. Therefore, while Ho and colleagues (43) were unable to detect Aβ, p-tau, or α-synuclein in any ocular tissue of AD or Parkinson's disease (PD) patients, considerably more independent studies in fact reported the presence of Aβ deposits in the retina and lenses (11,39,40,42,51,83) as well as identified p-tau (41) and α-synuclein (84) in the retinas of AD and PD patients, respectively. Future studies should apply suitable techniques and comprehensive examination of flat-mount retinas to study additional pathological hallmarks of AD in the retina.…”

“…While the hallmark pathologies of AD have long been established in the brain, their manifestation in the human retina is a recent finding (11,26,(39)(40)(41)(42). We previously identified Aβ plaque pathology in postmortem retinas of definite AD patients as well as in early-stage cases (40).…”

“…Subsequent studies have corroborated these findings by demonstrating the existence of retinal Aβ deposits, identifying increased Aβ peptides in the human retina by biochemical analysis (albeit to a lower extent than those seen in neocortical tissues), and, moreover, showing the presence of pTau in retinal tissues of AD patients (39,41,42). Although a few studies were unable to detect Aβ (41,43) or pTau (43) in the human AD retina, several independent groups confirmed their existence by applying specific tissue processing and immunostaining protocols and screening large retinal regions that had previously been overlooked (11,26,(39)(40)(41)(42). In a recent study, notable Aβ accumulation inside and around degenerating melanopsin-containing RGCs (mRGCs), photoreceptors known to drive circadian photoentrainment, was found in AD patients (26).…”

“…In addition to afflicting the brain, AD also affects the retina, a developmental outgrowth of the brain (12)(13)(14), possibly causing these symptoms. The retinas of AD patients display pathologies such as nerve fiber layer (NFL) thinning, retinal ganglion cell (RGC) degeneration, reduction of blood flow and vascular alterations, astrogliosis, and abnormal electroretinogram patterns (11,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). Among the many characteristics it shares with the brain, the retina contains neurons, astroglia, microglia, microvasculature with similar morphological and physiological properties, and a blood barrier (12-14, 34, 35).…”