Research continues to explore the cause and proliferation of Alzheimer’s disease (AD) including whether the eye can provide early clues to the condition. Delving further into this area, a recent investigation in South Korea suggests using retinal biomarkers as preclinical indicators of AD and related brain abnormalities in cognitively normal, older adults.¹

All 49 participants underwent complete ophthalmic exams, including SS-OCT, multifocal electroretinography, as well as Aβ positron emission tomography and an MRI. Data was collected from 2016 to 2017. Of the 49 participants, roughly half were women, and the volunteers were approximately 71 years old.

The cross-sectional study found an association between amyloid-β (Aβ) deposits and reduced thickness of the macula and RNFL, in addition to delayed implicit time as seen on multifocal electroretinograms. Additionally, researchers observed a connection between the ganglion cell complex–inner plexiform layer thickness and AD–related neurodegeneration in cognitively normal individuals.¹

A screening model based on these results showed a 90% diagnostic accuracy in detecting the Aβ deposits in these subjects.

The specific patterns of retinal changes may indicate the presence of different types of AD pathologic abnormalities: in vivo cerebral Aβ deposition and AD-neurodegeneration, investigators said.

The study also found that cognitively normal older adults with cerebral Aβ deposition had both structural and functional changes in the retina.

Compared with 33 cognitively normal individuals without Aβ deposition (Aβ−CN), the 16 participants with Aβ (Aβ+CN) showed reduced inner nasal macular thickness (308.9µm vs. 286.1μm) and RNFL, particularly in the inferior quadrant (133.8µm vs. 103.8μm).

In addition, the Aβ+CN group showed prolonged implicit time compared with the Aβ−CN group, and notably in ring five (41.3ms vs. 38.2ms).¹

In an invited commentary on the JAMA Ophthalmology study, Dilraj S. Grewal, MD, and Sharon Fekrat, MD, both of Duke University, suggested the differential association of neurodegenerative changes with specific regions of the retina merits further investigation since the ganglion cell–inner plexiform layer was similar while the inner nasal macular thickness was thinner in Aβ-positive individuals.² A layer-based analysis might be helpful to determine whether the layers of the retina are affected differently, in addition to a topographic region–based analysis, they suggested.²

The commentary authors also noted that individuals with the APOE4 genotype have a greater risk of developing AD and are more likely to have Aβ accumulation. As such, it would be helpful to know whether the results differed in those with APOE4 carrier status and subjects without this genetic marker.²

While the investigation’s model showed a high level of sensitivity at roughly 94%, specificity was relatively lower at about 79%, Drs. Grewal and Fekrat said.²

“Although these biomarkers are not yet ready for use in clinical practice, this study provides important data on both structural and functional retinal changes in preclinical AD,” the commentary authors wrote in their paper. “Although large, diverse population-based studies are needed to provide further insights into the long preclinical AD prodrome and further elucidate the role of retinal changes, these metrics bring us a step closer in our quest to developing retinal biomarkers in the detection of asymptomatic preclinical AD.”²

1.Byun MS, Park SW, Lee JH, et al. Association of retinal changes with Alzheimer’s disease neuroimaging biomarkers in cognitively normal individuals. JAMA Ophthalmol. March 25, 2021. [Epub ahead of print]. 2. Grewal DS, Fekrat S. Structural and functional retinal changes in preclinical Alzheimer’s disease. JAMA Ophthalmol. March 25, 2021. [Epub ahead of print].