Today, Alzheimer’s disease (AD) can only be definitely diagnosed after a person dies. But new research suggests the possibility of much earlier diagnosis with a simpler, less invasive method: eye exams.
In a recent in-depth analysis, research published in the journal Acta Neuropathologica details how changes in the retina correspond to brain and cognitive changes in Alzheimer’s disease patients.
“These findings may lead to the development of imaging techniques that would be able to diagnose Alzheimer’s disease earlier and more accurately,” says senior author Maya Koronyo-Hamaoui, PhD, professor of neurosurgery, neurology, and biomedical sciences at Cedars-Sinai in Los Angeles.
The Eyes Provide a Window to the Brain
The connection between the retina and the brain is well known to researchers. The retina is part of the central nervous system, made up of the light-sensing layers of nerve tissue that connect the eye and brain. But unlike the brain or spinal cord, the retina can be imaged directly, making it an ideal model for scientists. Much of what is known about the brain actually comes from studying this part of the eye, according to the National Eye Institute.
Scientists have been exploring how to use the imaging technology used in ophthalmology to measure levels of Alzheimer’s biomarkers in our eyes for several years now, says Percy Griffin, PhD, director of scientific engagement at the Alzheimer's Association.
“The ability to easily detect the biological hallmarks of Alzheimer’s in the eye is intriguing, in that it may provide the ability to detect the disease in a noninvasive manner, in earlier stages before symptoms appear,” says Dr. Griffin, who was not involved in the study.
It’s estimated that 500,000 Americans are diagnosed with Alzheimer’s each year, according to BrightFocus Foundation, a nonprofit dedicated to brain and eye research. Within 30 years, the number of U.S. adults over 40 living with dementia is projected to rise from 5.2 million people to 10.5 million, according to an analysis published in January 2022 in The Lancet.
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Researchers Used Eye and Brain Tissues From People With Dementia
Using human eye and brain tissues from deceased donor patients, researchers compared samples from donors with normal cognitive function to those with mild cognitive impairment at the earliest stages of Alzheimer’s disease and to those with later-stage Alzheimer’s disease dementia.
Retinas were analyzed for markers of inflammation and functional cell loss, as well as the level of different proteins associated with AD that were present in retinal and brain tissues.
A surplus of a protein known as beta-amyloid 42 was found in the retinas of people with MCI and AD, with the inner layers and peripheral parts of the retina showing the most pronounced accumulations.
In people with AD, abnormal levels of this protein clump together to form plaques that collect between neurons and disrupt normal cell function, according to the National Institute on Aging.
There was also an accumulation of beta-amyloid protein in the ganglion cells of the retinas of people with MCI and AD. Ganglion cells act as a “bridge” that connects retinal input to the visual processing center in the central nervous system.
People with MCI and AD also had a greater number of microglial cells — immune cells of the brain that attack bad proteins and infection. However, those cells were defective and didn’t behave in the same way as people with normal cognitive function, says Dr. Koronyo. “In people with mild cognitive impairment and Alzheimer’s disease, only about 20 percent of the microglia are engaging and doing their role of removing the toxic abnormal proteins,” she says.
Retinal Changes ‘Mimicked’ Brain Changes Tied to MCI and AD
Researchers also found specific molecules and biological pathways responsible for inflammation and cell and tissue death in the retinas of people with MCI and AD.
The changes observed in the retina correlated with changes in the parts of the brain that are responsible for memory, navigation, and the perception of time, according to the authors.
“Changes that were in the brains of people with MCI or AD were mimicked or predicted by changes seen in the retina,” says Koronyo. Retinal changes were detected even in patients who appeared cognitively normal or with very mild MCI, making those a possible early predictor of later cognitive issues, she adds.
The Next Step: Monitoring Cognitive Changes in Live Patients
These findings are very exciting because the next step would be to image live patients, according to the authors.
“Because these changes correspond with changes in the brain and can be detected in the earliest stages of impairment, they may lead us to new diagnostics for Alzheimer’s disease and a means to evaluate new forms of treatment,” said coauthor Keith L. Black, MD, chair of the department of neurosurgery at Cedars-Sinai, in a press release.
Technology Should Be Studied in Larger, More Diverse Populations
Dr. Griffin points out that this new research found higher levels of inflammation in the eyes of women compared to men. “Given that more women over the age of 65 are living with Alzheimer’s dementia than men, we need to understand these sex differences and how they contribute to risk,” he says.
“Research in this space is still in the early stages, and this tool must be studied in larger, more diverse populations to understand how or if retinal imaging may be a useful Alzheimer’s screening tool in all populations,” says Dr. Griffin.
Could Blood Tests, Rather Than the Retina, Be the Future of Diagnosing and Monitoring AD?
“The idea that there’s a link between the eye and Alzheimer’s disease has been around for a while,” says Constantine Lyketsos, MD, a professor of psychiatry who specializes in dementia at Johns Hopkins Medicine in Baltimore and was not involved in this study.
The connection found in this study — between Alzheimer’s disease progression (also called pathology) in the brain and biomarkers in the retinas — is interesting, but Dr. Lyketsos is skeptical that it will change how AD is diagnosed.
“The potential for this to eventually be used to study the eye in a living person is intriguing, but this technology would also be competing with a variety of other methods that we know are pretty accurate in telling us how much pathology is in the brain of someone. I’m not sure that this is really going to change the field that much,” he says.
The gold standard for detecting AD remains autopsy. But there are very good ways to measure probable Alzheimer’s disease progression in living people, including brain imaging studies, PET scans, and MRIs, says Lyketsos.
“We are also very close to having blood tests that tell us how much brain AD pathology an individual has,” he says. This test, described in a paper published in December 2022, can measure levels of a toxic protein that is highly correlated with developing Alzheimer’s disease (AD) years before any symptoms of cognitive impairment appear.
Researchers believe that the simple blood test could inexpensively give a read of what’s going on in the brain and could be used to identify people at risk — without a lumbar puncture or expensive imaging.
“I think the blood tests are going to be much simpler and easier to use because studying the eye requires specialized equipment,” says Lyketsos.
“The Alzheimer’s Association believes in the importance of identifying easy-to-use, noninvasive, relatively inexpensive methods for early detection and diagnosis of Alzheimer’s disease and has supported a considerable amount of research in this area,” says Griffin. To that end, the organization has established the Global Biomarker Standardization Consortium (GBSC) to standardize and validate biomarker tests for use in clinical practices around the world, he says.