Current Status of Retinal Diagnostics In Alzheimer’s Disease

The use of retinal markers for the early detection of biological changes in Alzheimer’s disease is becoming increasingly promising with the advent of new treatments for this neurodegenerative disease and the ever-increasing number of elderly individuals in the population. Since the retina is a part of the central nervous system that can be easily visualized by various imaging techniques, it is studied for the early detection of Alzheimer’s disease.

What the Research Says

We report on a cross-sectional study (NCT03233646) in 37 patients with amnestic mild cognitive impairment (aMCI) and 33 patients with Alzheimer’s disease (AD). In this study, non-invasive eye imaging of the retina/choroid could serve as a surrogate marker for cerebral neurodegeneration. We correlated retinal/choroidal microvascular parameters with cerebral atrophy as determined by automated volumetric brain MRI (NeuroQuant).

Why It Matters

Early detection of Alzheimer’s disease is critical as available therapies are disease- and risk- modifying and are most effective before significant brain atrophy has occurred. Current methods for detection and confirmation of Alzheimer’s disease pathophysiology are accurate, but expensive, invasive (contrast media injected intravenously) and not readily available to the majority of health care providers.

The retina is a part of the central nervous system which can be easily imaged by current technology. The retina’s microvasculature, especially the superficial capillary plexus of the retina, shares embryonic features with the microvasculature of the neural tube of the brain. Thus, noninvasive imaging of the retina could serve as a novel surrogate marker for the detection of biological alterations in Alzheimer’s disease as well as for the monitoring of the degree of neurodegeneration and of therapeutic effects in patients with this disease.

A number of challenges will arise in the implementation of retinal diagnostics on a large scale and their impact on the healthcare system as a whole. There are costs to new technology, new staff to train and the follow up investigation of newly identified patients. Workforce planning for the implementation of retinal diagnostics will require input from ophthalmologists, optometrists, primary care physicians and neurologists to develop effective referral patterns and models of care. There is also the potential for health care disparities, as the currently validated technologies have been primarily validated in a predominantly white population. Further work is required to validate the use of retinal diagnostics in a diverse population.

Key Study Findings & Imaging Correlations

Superficial capillary plexus (SCP) perfusion density (PD), superficial and deep capillary plexus (SCP and DCP) vessel density (VD), and foveal avascular zone (FAZ) area were measured using optical coherence tomography angiography (OCTA). Hippocampal, superior lateral ventricle (SLV), and inferior lateral ventricle (ILVentricularSize) volumes were measured using brain MRI and used as end points for neurodegeneration.

• Amnestic MCI Cohort: Lower hippocampal volume significantly correlated with a larger FAZ area (indicative of capillary dropout) and decreased PD and VD in the central 3 mm macular zone. Furthermore, ventricular expansion (indicative of cerebral atrophy) correlated with microvascular decline: SLV volume expansion associated with decreased 3 mm circle PD, and ILV expansion associated with decreased 6 mm inner ring PD.
• Alzheimer’s Disease Cohort: Significant negative correlations were found between ventricular expansion (both ILV and SLV) and retinal microvascular parameters (PD and VD) across multiple 3 mm and 6 mm macular zones. Notably, hippocampal volume did not significantly correlate with OCTA metrics in AD patients, potentially because hippocampal atrophy reaches a plateau phase by the time patients exhibit mild dementia (mean MMSE 22.4).
• Cohort Comparisons: Patients in the AD group demonstrated significantly lower 3 mm macular VD, thinner ganglion cell-inner plexiform layers (GC-IPL), and larger ILV volumes than those in the aMCI group, reinforcing these metrics’ utility in tracking disease progression.
• Structural Metrics: Traditional structural thinning markers—including central subfield thickness (CST), retinal nerve fiber layer (RNFL) thickness, and the choroidal vascularity index (CVI)—did not significantly correlate with brain volumetric parameters in either cohort.

Who It Affects

Patients: This could be the early detection of Alzheimer’s disease in older people with memory problems and their families. People with a history of vascular disease, diabetes, glaucoma or age-related macular degeneration as retinal changes in these conditions can be confused with Alzheimer’s disease.

A second set of individuals and groups who would be affected by the use of retinal diagnostics for screening of risk of dementia and monitoring of patients with Alzheimer’s disease are the Clinicians, particularly the primary care physicians, and the Neurologists. The findings of this study can be applied to the screening of patients with mild memory complaints for early diagnosis and treatment with currently available disease-modifying and risk-reducing therapies before significant amount of brain atrophy has occurred. The primary care physicians can use the retinal diagnostics for screening for risk of dementia in their patients, and the Neurologists can use it for monitoring their patients with Alzheimer’s disease for any potential side effects from the therapies as well as for neurodegenerative progression. The retinal diagnostics can provide a quick and non-invasive screening tool in conjunction with volumetric MRI for assessing and monitoring the neurodegenerative progression in patients with aMCI and AD. The study provided the proof of concept for the use of retinal imaging in screening and monitoring of neurodegenerative diseases. The decline in retinal microvasculature is associated with brain atrophy in Alzheimer’s disease, and the OCTA metrics of the retinal microvasculature (PD and VD) are more sensitive to early brain atrophy in AD than the OCT metrics of the retinal structure.

Healthsystems and payers: Is there potential for cost savings for a healthsystem that uses retinal imaging for the early detection of Alzheimer’s disease and allows for the early initiation of therapy and its monitoring and adjustment as needed. Are there potential savings from reduced numbers of referrals to specialists for possible dementia and for the cost of care of people with a diagnosis of dementia. What would be the cost of needed evidence (for clinical utility, cost-effectiveness, and patient outcomes) to support a claim for reimbursement by healthsystem payers for a retinal imaging test and its follow-up diagnostic and monitoring tests and treatments.

Researchers and companies developing diagnostic devices: There will be an increased demand on companies developing new diagnostic devices (hardware and software) as well as on researchers applying artificial intelligence (AI) for image analysis. However, the methods have to be validated, the used metrics have to be standardized and the products have to receive approval by the relevant health authorities before they can be brought to the market.

What Changes

• Retinal imaging becomes part of a staged screening pathway: low-cost, noninvasive retinal tests used early to identify people who need confirmatory biomarkers or specialist referral.
• Clinical workflows shift: eye-care practices and primary care clinics develop protocols for performing, interpreting, and referring based on retinal findings, with attention to common comorbid eye diseases that can confound results.
• Integration with blood-based biomarkers and digital tools: retinal imaging is combined with blood tests and algorithmic risk scores to improve specificity and guide individualized care plans.
• Policy and payment models evolve: payers consider covering retinal screening when evidence demonstrates improved patient outcomes, cost savings, or better targeting of expensive treatments.

The Present Retinal Technologies Fall Into Several Categories.

Existing Retinal Technologies for the Screening of Neurodegenerative Disease can be broadly categorized into several groups. Optical Coherence Tomography (OCT) imaging of the retina using a variety of different protocols can allow for the assessment of the thickness of the individual layers of the retinal nerve cells. OCT Angiography (OCTA) can also allow for high quality imaging of the superficial capillary plexus allowing for the assessment of perfusion density (PD) and vessel density (VD). The wide-field fundus photography and fundus autofluorescence imaging have been used for the assessment of the larger retinal vasculature and for the detection of retinal deposits associated with neurodegenerative disease. There are also a number of emerging optical technologies currently under investigation for their potential to image Alzheimer’s disease associated molecules such as amyloid and tau in the retina.

There are a few early studies exploring the use of retinal diagnostics for the diagnosis of Alzheimer’s disease and the associated barriers to their application. This study found that in older individuals with memory loss changes in the retinal microvasculature detected by OCTA may help to identify individuals at risk of dementia due to Alzheimer’s disease before the onset of brain atrophy. However, the use of retinal imaging as a triage test is limited to older individuals with memory concerns and absence of retinal findings would not rule out a diagnosis of Alzheimer’s disease in the early stages of the disease. The study also highlights a number of other factors that must be taken into account when interpreting retinal imaging in older individuals including age-related changes, other ocular diseases (e.g. cataract) and systemic vascular disease.

Limitations

The majority of the currently measurable retinal features which have been found to change in Alzheimer’s patients, have considerable overlap with normally aging and ocularly diseased individuals. Therefore, for each feature, it must be determined how Alzheimer’s patients differ from normally aging individuals. Additionally, the currently large inter-device and inter-method variability must be decreased, particularly for features that are analyzed by sophisticated computer algorithms and require very large amounts of data for ‘training’ in a non-biased manner to measure retinal features. Future work with retinal imaging in Alzheimer’s will therefore primarily focus on the validation of the use of retinal imaging to alter the management of patients with neurodegenerative diseases and to alter the outcomes of such patients.

Operations, Logistics, and Limitations

Implementing Retinal Tests for Neurodegenerative Diseases: Operational Challenges, Logistics and Limitations for Health Systems. While there are many issues to consider, for example, training of non ophthalmic staff to obtain quality images, establishing a reading center or software-based reading center and clarifying the referral pathway, decisions for Health Systems regarding screening for Alzheimer’s risk will involve where to conduct the screening, for example primary care, Memory Clinics and/or Eye Clinics and how to pay for the test and its follow-up. People living in rural or other isolated areas will require access to portable imaging and teleophthalmology in order to have an equal opportunity to benefit from retinal testing.

Looking Forward

As such, in the short term, retinal imaging is likely to be used as part of a multi-modal assessment of risk for Alzheimer’s disease. Screening blood tests for phosphorylated tau and amyloid, as well as a variety of other cognitive tests and clinical risk factors, will be used to select patients who would benefit from more in-depth imaging. The results from the initial retinal imaging and blood test could be used to select patients for further imaging or referral to a specialist for more in-depth assessment and treatment.

Future Research

Future studies are needed to standardize the use of currently available as well as emerging optical imaging techniques and corresponding clinical endpoints. Additional prospective studies will be needed to assess change in retinal microvasculature and retinal structure in patients with AD and other neurological disorders over time, and to correlate findings with clinical outcomes and treatment response. Studies are also needed to assess the health services research issues including use, cost, and access to novel screening tests. Ultimately, payment and regulatory frameworks will need to be developed that are consistent with available evidence on novel screening tests.

Implications for Clinicians and Healthsystem Leaders

However, in order to translate the potential into practice a number of steps are required. The tests need to be more validated, used in combination with other biomarkers and policies and their implementation need to be developed and carried out in a fair and accessible manner. With the potential for early intervention and improved outcomes for people with Alzheimer’s disease, using retinal screening as a triage tool could be an important step forward in the management of the condition as more disease-modifying treatments for Alzheimer’s become available for clinical use.

Reference

1. Zhao W, Robbins CB, Grewal DS, et al. Correlating retinal and choroidal vascular parameters with volumetric MRI in Alzheimer’s disease and amnestic mild cognitive impairment. BMC Ophthalmol. 2025;25(1):365. Published 2025 Jul 1. doi:10.1186/s12886-025-04157-x