Imaging the retina: a non-invasive, accessible way of studying Alzheimer’s disease

The eyes are often called “the windows to the soul” — but what if they could also be windows to the brain?

Alzheimer’s disease (AD)-related changes have been observed in both the retina and brain because the retina shares anatomical and functional similarities with the central nervous system (CNS). Studies in both transgenic mouse models of AD and human post-mortem retinal tissues from AD donors have demonstrated these parallels.

Dr. Joanne Matsubara, a professor in the UBC’s Department of Ophthalmology and Visual Sciences and lead investigator for the UBC Research Excellence Cluster in Vision, studies how the retina can be used to detect and monitor Alzheimer’s disease.

Building on this work, Dr. Printha Wijesinghe joined Dr. Matsubara’s lab as a postdoctoral fellow to advance Alzheimer’s research.

“The retina is a direct extension of the central nervous system and mirrors many of the pathological processes observed in the brain,” says Dr. Wijesinghe.

The beginnings of eye modeling in AD

In the mid-1980s, researchers discovered significant optic nerve degeneration in the post-mortem eyes and brains of people with Alzheimer’s disease compared with age-matched controls. Studies continued into the early 1990s, but these early studies on visual function of AD patients could not demonstrate AD-associated changes in electroretinograms (ERGs), which puzzled many scientists.

In the mid to late 1990s, several labs, including Dr. Matsubara’s, reported concurrent amyloid-beta (Aβ) or Aβ-like deposits in the brain and eye tissues of newly developed AD mouse models.

“This opened the door to experimental studies that continue today to help us understand what is happening in the eye,” Dr. Matsubara explains. “The retina, cornea and lens have all shown similarities to the progression of brain changes in mouse models of Alzheimer’s disease.”

Looking beyond the brain

The retina is an attractive target for early AD screening because of its accessibility for non-invasive imaging techniques. Through these techniques, several AD-associated retinal biomarkers have been identified, including the thinning of the retinal nerve fiber layer (NFL), which has been observed consistently in AD patients using optical coherence tomography (OCT).

“This thinning correlates with cognitive decline and disease progression, and importantly, may be detected before clinical symptoms appear,” Dr. Wijesinghe notes.

Researchers have identified Aβ plaques, a hallmark of AD, in both patients and animal models. They have also observed changes in the retina’s blood vessels, including reduced vessel density, decreased blood flow and increased Aβ deposits. These changes may indicate broader problems with blood vessel function and the brain’s ability to clear Aβ, both of which are linked to Alzheimer’s.

Beyond the retina, body fluids can also provide valuable clues about disease processes. Cerebrospinal fluid (CSF) provides direct insight into the brain and nervous system; however, its collection is highly invasive. Blood-based biomarkers have recently received FDA approval for use in specific clinical contexts, highlighting their growing value in diagnosis and management of AD. Nevertheless, blood biomarkers may benefit from complementary information that improves disease specificity, captures additional biological processes, or enables longitudinal monitoring.  Tear fluid offers a promising adjunct because it can be collected easily and non-invasively, while still capturing molecular changes associated with the central nervous system.

“As such, tear-based biomarkers have the potential to complement blood-based assays and provide additional insights into disease mechanisms and progression,” says Dr. Wijesinghe.

Investigating the inner blood-retina barrier

Structurally and functionally similar to the blood brain barrier (BBB), the inner blood-retina barrier (iBRB) is essential for maintaining retinal homeostasis and may mirror BBB alterations that underlie the disease processes.

“We are hopeful that structural changes at the inner blood-retina barrier (iBRB) may serve as future diagnostic markers for Alzheimer’s disease,” Dr. Wijesinghe explains. “Our research highlights the value of studying wholemounts, which allow us to visualize interactions among neurons, glial cells, and the retinal blood vessels that are difficult to see in traditional brain tissue cross-sections.”

In a recent study published in the Alzheimer’s & Dementia journal, Drs. Matsubara and Wijesinghe used 3D imaging of retinal wholemounts to identify several protective mechanisms that help clear Aβ accumulation. In healthy tissue, these mechanisms include support from the glymphatic system, as well as immune cells. They also observed the involvement macrophage-like cells that bind and remove toxic soluble forms of Aβ. However, these protective mechanisms appeared to be impaired in tissues from people with Alzheimer’s.

This study marks the first use of ex vivo 3D retinal imaging to examine these processes at the iBRB. The findings show that imaging method (surface versus cross-sectional) can influence the interpretation of disease-related changes. For example, distinct differences in AD-related changes emerged between human retinal wholemounts and mouse retinal cross-sections. The ability to use non-invasive retinal imaging methods holds significant promise in clinical translation.

“As imaging technologies continue to advance, structural and molecular alterations at the iBRB may eventually be detectable in vivo, paving the way for early, accessible and potentially eye-based diagnostic tools for neurodegenerative diseases such as Alzheimer’s,” Dr. Wijesinghe explains.

Comparing retinal imaging to traditional methods

Research on retinal imaging for Alzheimer’s disease is still evolving, and its sensitivity and specificity have yet to be compared fully with brain imaging or CSF analysis. However, Dr. Matsubara highlights that the key advantage of retinal imaging is that it is non-invasive, which makes it more accessible.

“Retinal imaging is quick, painless and uses harmless light to capture detailed images of the eye—no needles, dyes, or radiation are required,” Dr. Matsubara explains. “In contrast, brain scans require expensive equipment and often injections, while spinal taps require a needle in the lower back and can cause discomfort, although they are generally safe.”

Retinal imaging therefore has the potential to make the early detection and monitoring of Alzheimer’s more patient-friendly. Combined with blood-based and potentially tear-based biomarkers, retinal imaging holds significant promise as a non-invasive approach to studying and detecting Alzheimer’s.

Looking ahead

When asked about the next big research focus for her laboratory, Dr. Matsubara highlights the study of tear fluid.

“We are investigating tear fluids as another accessible biofluid, alongside blood and CSF, to capture information that may improve the early diagnosis of Alzheimer’s disease and help us better understand how the disease progresses over time,” she says.