The retina in Alzheimer’s disease: Anatomy and Pathology

AbstractGrowing evidence suggests that Alzheimer’s disease (AD) pathology is not confined to the brain but also appears in the neurosensory retina. Perceived as an extension of the brain, the retina is visible directly and noninvasively at the vascular, cellular and molecular resolution. Aβ accumulation, vascular amyloidosis, hyperphosphorylated (p)tau, microgliosis, astrogliosis, Müller glia changes, abnormal electroretinography patterns, and neuronal degeneration have all been described in the postmortem retina of AD patients, including in early‐stage cases. Although a few studies were unable to consistently repeat these findings, increased proportion of positive studies from subsequent histological, biochemical, and imaging studies validated the original findings. Several studies further provided data suggesting that the brain and retina follow a similar trajectory during AD progression, potentially due to their common embryonic origin and anatomical proximity. A host of retinal vascular abnormalities including reduced blood flow, foveal avascular zone and arteriole‐to‐venule ratio were observed by in vivo fundus imaging, optical coherence tomography (OCT) or OCT‐angiopathy in preclinical, prodromal and clinical AD patients. Further, retinal vascular platelet‐derived growth factor receptor‐β (PDGFRβ) expression and pericyte loss have been associated with retinal vascular amyloidosis and cerebral amyloid angiopathy in mild cognitively impaired (MCI) and AD patients. A recent proteomics profiling study revealed common molecular signatures in the AD retina and brain, with enriched pathways related to inflammation, vascular and photoreceptor vulnerability. Novel imaging techniques, such as curcumin fluorescence, have correlated increases in retinal amyloid burden with brain amyloid PET load and hippocampal atrophy in patients, and together with vascular changes predicted cognitive deficits. This perspective provides an overview on the evidence of AD pathology in the retina and current gaps in knowledge. Future studies exploring retinal pathology in AD and other neurodegenerative diseases may fundamentally contribute to the development of validated retinal biomarkers for improved noninvasive disease diagnosis and monitoring.