Conclusion
With the number of AD patients estimated to triple by 2050 (Alzheimer’s Association, 2019), a reliable, noninvasive and affordable diagnostic technique suitable for widespread clinical use is urgently needed. In recent years, a radical idea has emerged that AD pathology in the brain can also manifest and perhaps be mirrored in the retina. Indeed, the identification of hallmark Aβ deposits in the retina of patients and numerous animal models and their correlation with pathology in the brain have fueled this field of neuro-ophthalmology in AD. Moreover, mounting evidence now supports the existence of diffuse, classical and neuritic-like plaques, pTau aggregates, Aβ42 fibrils, protofibrils, and oligomer-like structures, pericyte loss, vascular Aβ40 and Aβ42 accumulation, inflammation and neurodegeneration in the retina of AD patients (Alexandrov et al., 2011; Koronyo-Hamaoui et al., 2011; Schön et al., 2012; Tsai et al., 2014; La Morgia et al., 2016; Koronyo et al., 2017; den Haan et al., 2018; Grimaldi et al., 2018; Hadoux et al., 2019; Schultz et al., 2020; Shi et al., 2020). Despite many recent successes, several limitations including the scarcity of retinal tissue from people with neuropathological data and the application of non-conventional histological and biochemical techniques to examine AD effects in various topographical regions, has historically restricted the knowledge in this field. Future investigations, involving brain biobanks with extended collection of ocular tissues, will allow researchers to determine how early AD pathological processes occur in the retina, their extent, distribution, and relationship to brain pathology.
Histological and biochemical examinations of postmortem retina from AD patients and animal models have proven invaluable in deciphering the pathological burden of disease hallmarks, susceptible retinal layers and cell types, and putative molecular pathways linked to retinal atrophy and functional deficits. Nevertheless, there is still lack of understanding of the impact of Aβ and tau pathologies on retinal cell types; some effects, including nerve fiber thinning, neuronal loss and vascular changes, may not manifest in early stages of disease and may not be specific to AD. For instance, reduced NFL, macular, and foveal thickness have also been observed via OCT examinations of Parkinson’s disease (PD) patient retinas as compared to normal controls (Inzelberg et al., 2004; Altintas et al., 2008; Hajee et al., 2009; Cubo et al., 2010; Moschos et al., 2011, 2012; Shrier et al., 2012; Adam et al., 2013; Moreno-Ramos et al., 2013; Satue et al., 2013; Moschos and Chatziralli, 2017).
Notably, according to the 2018 NIA-AA research framework, the presence of Aβ deposits is a requirement for Alzheimer’s pathological change diagnosis and should be considered in early screening efforts and recruitment of individuals for clinical trials (Jack et al., 2018). The ability to detect and quantify Aβ deposits and related pathologies via noninvasive retinal imaging along with sensitive, routine, minimally invasive plasma AD biomarkers show great promise for diagnostic screening, monitoring of progression, and assessment of therapeutic efficacy (Hampel et al., 2018; Baldacci et al., 2020). The work described here combined with future advances may lead to clinical translation, discrimination of pathophysiological phenotypes during the AD continuum, and eventually a highly anticipated cure for this destructive disease.
Future investigations should focus on standardization of histological techniques, identification of early AD biomarkers in the retina, their spatiotemporal profiles, and enhancing the sensitivity of retinal imaging modalities for detection of these pathological indicators in this new and expanding field of Alzheimer’s retinopathy.