​Your eyes may be a window into early Alzheimer's detection

It is often said that eyes are windows to the soul, but according to recent research, they may also reveal early signs of Alzheimer’s disease, a neurodegenerative ailment that affects more than six million people in the United States and 55 million people worldwide.

A seven-year analysis has connected physical changes in a region of the eye called the retina to what happens in the brain during Alzheimer’s, starting from its earliest stages when patients exhibit only mild cognitive impairment.

“Alzheimer’s disease starts very early on in terms of the pathological changes, which can occur decades before symptoms do,” says Maya Koronyo-Hamaoui, a neuroscientist at Cedars Sinai Medical Center in Los Angeles who led the new study and collaborated with researchers in Italy and Australia. If clinicians could reliably diagnose the disorder in this period before symptoms appear, they could try interventions to slow down its progression. New drugs on the market, like lecanemab, for example, target patients with mild impairment before the symptoms become irreversible.

Located in the back of the eye, the retina translates light into electrical signals that travel to the brain. Examining the eye may seem an unlikely strategy for Alzheimer’s screening, but in fact “it’s the only part of the central nervous system that you can see directly in a living person, [which isn’t obscured by bone], so people have been looking at the eye in Alzheimer’s disease for quite a while,” says Alan J. Lerner, a neurologist with University Hospitals Cleveland Medical Center in Ohio who has treated patients with dementia for more than 30 years.

Koronyo-Hamaoui’s team found that higher levels of the beta-amyloid protein—a hallmark of Alzheimer’s disease—in the retina corresponded to higher levels in the brain and more severe cognitive decline. In fact, the amount of this misfolded protein in a patient’s retina was better at predicting how they had scored on cognitive tests than tests revealing the density of brain plaques—clumps of beta-amyloid protein—present in the brain.

Based on this new work—which was done using cadavers and tissues samples—several clinical trials are underway to determine if measuring amyloid deposits in the retina is an accurate way to diagnose early stage Alzheimer’s disease in living patients.

Lerner, who was not involved in the research, calls such efforts to develop diagnostic tests “a sea change” in how the scientific community regards Alzheimer’s disease. “We’re really moving in recent years from a clinical diagnosis, based on symptoms, to a biological definition, based on biomarkers,” or measurable signals such as fasting blood sugar levels for diabetes.

What the retina reveals

The post-mortem study, which looked at retinal and brain tissue samples from 86 human donors, examined potential biomarkers in the retina and linked them to known indicators of Alzheimer’s disease like amyloid plaques (between neurons) and neurofibrillary tangles (inside neurons). They also looked at the relationship between retinal damage and cognitive decline. In 39 cases, the researchers assessed the retina and brain of the same subject, making a direct comparison possible. Donors ranged from healthy individuals to those with mild cognitive impairment (MCI) to Alzheimer’s disease patients with dementia.

This is the first quantitative analysis of the retinas of MCI patients, which is an important population because these people are experiencing the earliest symptomatic stages of Alzheimer’s disease, says Yosef Koronyo, a neuroscientist also at Cedars Sinai Medical Center, who developed many of the techniques used in the current research. Changes in the retina between healthy individuals and this group could identify patients who haven’t advanced to dementia, while additional changes as Alzheimer’s worsens could track its progression.

To visualize these biomarkers, Koronyo-Hamaoui and her team labeled them with compounds that glow in the presence of light—a technique called immunofluorescence. “Then you can count them or count the area they cover, and this gives you a lot of information about the pathology,” Koronyo-Hamaoui says. The researchers guessed that just as Alzheimer’s disease affects some regions of the brain more than others, the disease damages some areas of the retina earlier or later in the disease’s progression. And, as they predicted, many biomarkers are first elevated in the inner layer of the retina—the one exposed to light—and particularly in the regions furthest from the center of the eye. Understanding which areas are impacted first helps physicians focus on specific locations when providing eye exams.

Levels of “beta-amyloid in the retina spike really early on and give you the biggest separation between normal cognition and MCI,” says Koronyo-Hamaoui. Compared to healthy controls, the retinas of MCI patients had five times the amount of beta-amyloid; levels in Alzheimer’s disease patients were nine times higher.

In Alzheimer’s disease, the buildup of plaque and other detritus in the brain is thought to trigger an immune response—leading to runaway inflammation, the death of neurons, and abnormal connections between them. So Koronyo-Hamaoui and her colleagues also looked at the immune cells in the retina, which normally protect the system from pathogens and injury.

Spurred by the accumulation of excess beta-amyloid, the retinas of MCI and Alzheimer’s disease patients contained more activated immune cells compared to healthy controls. But the researchers noticed that these cells were 80 percent less efficient at clearing away the toxic proteins. “It becomes this vicious cycle,” says Koronyo-Hamaoui. “The whole environment is injured and diseased.” The immune cells also become defective, but whether this drives or is a consequence of the disease is unknown.

Similarly, the scientists mapped out other symptoms of disease in the retina and their relationship to each other as well as to those of the brain—like the thinning of retinal tissue, which reflects the amount of cell death, and dysfunction of support cells like astrocytes that keep the retina healthy.

For Ruogu Fang, a medical AI researcher at the University of Florida in Gainesville who uses machine learning to detect neurodegenerative diseases, this work confirms the importance of the retina in Alzheimer’s disease. “It adds another layer of confidence,” she says, “to show that anatomical, molecular, cellular and even functional changes in the retina can reflect changes in the brain.”

From the lab to the doctor’s office

The team also compared protein levels in the retinas and brains of healthy individuals versus Alzheimer’s disease patients. Among their findings: Levels of proteins important for maintaining the retina’s light-detecting cells drop in Alzheimer’s patients, implying photoreceptors are particularly vulnerable to the ravages of this disease, and providing a biological mechanism behind the vision problems of some patients.

Overall, a picture is developing that connects amyloid buildup to inflammation and to neural degeneration and ultimately cognitive decline and dysfunction. But the researchers are most excited about the clinical applications of retinal scans to diagnose and track Alzheimer’s disease, including as a tool to assess the effectiveness of potential interventions to treat it.

For the immunofluorescence test, a patient consumes compounds that are selectively absorbed by amyloid deposits in the eye, and then the physician shines a light on the retina and takes a photograph. “It’s non-invasive, with minimal impact on the patient,” Koronyo-Hamaoui says.

These scans would also provide more information than tests based on identifying biomarkers in the blood. “You’ll be able to see, with micrometer resolution, what's going on between the astrocytes and the blood vessels, for example,” says Koronyo. In blood, on the other hand, “you cannot see structures; you cannot say if it’s plaques” or if changes are occurring inside the cells, adds Koronyo-Hamaoui.

Lerner, however, says there are many hurdles between biomarker development and its use in clinical practice. “The researchers did an enormous amount of work and have proven pretty definitively that the process in the retina mirrors and marches in lockstep with clinical and pathological changes in the brain,” he says. “But making the leap to say, ‘Good, we're going to use the retina as a biomarker,’ is maybe a little premature.”

Fang agrees, noting that the research used the eyes and brains of post-mortem subjects, while signals from living patients may be different. An initial step may be to test the degree of thinning of the retina, which Koronyo-Hamaoui’s team has shown is related to Alzheimer’s disease-related brain atrophy. “Atrophy in the retina can be imaged through optical coherence tomography, which is already available in ophthalmology clinics and at hospitals,” says Fang.