Alzheimer’s (AD) is a severe neurodegenerative disorder and a significant cause of worldwide morbidity and mortality. While the hallmark signs of AD, cerebral amyloid β-protein (Aβ) plaques and neurofibrillary tangles (NFTs) comprised of hyperphosphorylated (p)Tau, are necessary for a definitive AD diagnosis, they have been shown to precede clinical dementia onset by decades. Retinal imaging offers an accessible, non-invasive way to visualize and monitor central nervous system targets, including AD pathology, with vascular, cellular, and molecular resolutions.
Early studies identified AD-specific pathology, including Aβ deposits, pTau, and NFTs, in the postmortem retinas of AD patients. Subsequent studies have demonstrated that AD manifestations in the retina are similar to those observed in AD brains, including the accumulation of Aβ peptides and plaques, pTau inclusions, gliosis, and pericyte and neuronal degeneration, and are often detected in the superior and inferior temporal peripheral retinal regions. Additionally, the retinal amyloid burden has been found to correlate with cerebral amyloid load, hippocampal and whole gray matter atrophy, and verbal memory deficits in living AD patients.
A new comprehensive study published in the journal Acta Neuropathologica has provided significant insights into the impact of AD pathology on the retinas of individuals with mild cognitive impairment (MCI) and AD at the molecular, cellular, and structural levels. The study conducted by a team of researchers from the University of Eastern Finland involved the analysis of retinal tissue samples obtained from 88 individuals, including 36 AD patients, 24 MCI patients, and 28 cognitively normal (NC) controls.
The team used proteome analysis to identify AD-specific profiles for the retina and three brain regions, finding the most significant similarities between the retinas and temporal cortices. Proteins implicated in the activation of inflammatory and apoptosis-necrosis pathways, as well as the inhibition of mitochondrial and ribosomal machinery, were shown to be linked with those identified as differentially expressed proteins (DEPs) across seven AD brain datasets. Degeneration in the AD retina has also been found to affect photoreceptor-rich pathways selectively.
In the retinas of individuals with moderate cognitive impairment and Alzheimer’s disease, researchers discovered new intraneuronal A oligomers (AOi). They discovered that the temporal and geographic distribution of these AOi species and total A42 forms coincided with increased gliosis and atrophy in the retina. The presence of retinal A42, S100+ microgliosis, and atrophy corresponds with the severity of Alzheimer’s disease neuropathology; except for AOi, all retinal disorders match Braak staging. Women had greater levels of retinal IBA1+ microgliosis than males, while retinal A42 and microgliosis had the highest relationships with cognitive status regardless of gender.
A distribution map of retinal biomarkers demonstrated that biomarkers were primarily localized in the inner retina and distinct retinal subregions throughout the sample. At the early stages of MCI, retinopathies accumulated more heavily in the inner layers and peripheral subregions, whereas retinopathies progressed more in the later stages of AD dementia. The peripheral has greater A42 density than the central retina, indicating that A42 aggregates to plaques more quickly in the periphery. Yet, individuals with MCI or AD had much more GFAP+ microgliosis in central retinal subregions, particularly surrounding the optic disc.
Several histological investigations have found that the retinas of AD patients exhibited more A+ deposits, glial cells (GFAP+ and IBA1+), and apoptotic cells (CCasp3+) than NC controls. Another study found a significantly higher proportion of A immunoreactive region and IBA1+ microgliosis in the central retina of AD patients than in NC controls.
These prior investigations, together with the current one, imply that the most severe abnormalities in AD retinopathy occur in the retina’s peripheral subregions and inner layers and that this progression follows a temporal and geographic pattern.MCI retinas had far higher levels of A42, a marker of brain AD pathology, than NC retinas. This was substantially linked with the severity of A plaques in the entorhinal cortex, a brain area crucial in memory and cognition.
Despite having more microglial cells actively consuming A, the number of microglial cells actively swallowing A was lower in these persons. Ladies with Alzheimer’s disease were likelier than males to have retinal microgliosis. Brain A pathology, tauopathy, and atrophy were all associated with retinal A42, S100 calcium-binding protein B+ microgliosis, and atrophy, and the majority of retinal disorders corresponded to Braak staging. Although additional retinal biomarkers were linked to cognitive scores, the most significant associations were shown with A42, far-peripheral AOi, and microgliosis.
