Unlocking health mysteries

Image by Jennifer Toomey / MJH Life Sciences using AI

Alzheimer's disease (AD) is the leading cause of dementia, with approximately 6.5 million individuals in the US aged 65 years or older currently living with AD. It was also ranked as the sixth-leading cause of death in 2022. Projections indicate that the number of individuals in this age group affected by AD could reach 12.7 million by 2050.^1,2

AD is a neurodegenerative disease characterized by neuronal loss in the cerebral cortex and the formation of extracellular plaques. The plaques consist of amyloid-β (Aβ) protein deposits and the buildup of hyperphosphorylated tau proteins, which form neurofibrillary tangles.

Although AD is widely known for its neurodegeneration in the hippocampus and the entorhinal cortex, studies have shown that there are also changes to the retina.^1,3 Risk factors for AD include age, genetic alterations, and mutations in the precursor to the Aβ protein. Optical coherence tomography (OCT) may be a noninvasive tool used to predict AD through the assessment of retinal changes.

Basis for OCT

The connection between brain and retinal pathology has led to the development of imaging tools aimed at noninvasively detecting and monitoring signs of neurodegenerative diseases in living patients. OCT is one such tool, using reflected light to produce high-resolution, 2-dimensional cross-sectional images and 3-dimensional volumetric measurements. Within OCT, the retinal nerve fiber layer (RNFL) and the ganglion cell layer (GCL) are frequently assessed, providing valuable insights into conditions like diabetic retinopathy, macular degeneration, and glaucoma (Figure).

Retinal Layer Segmentation as Seen on an OCT Scan. (Image courtesy of Heidelberg Engineering)

Moreover, OCT has emerged as a diagnostic aid for neurodegenerative diseases such as AD, with studies extensively reporting the degeneration of retinal ganglion cells (RGCs) and RNFL thinning in patients with AD.3 Notably, these structural changes captured by OCT align with the observed decline in visual and cognitive function in patients with AD, adding further credence to OCT’s potential as a diagnostic tool for the disease (Figure).³

Visual changes in AD

Although AD is widely known for its impact on memory, studies have shown that it also has an impact on visual acuity. Salobrar-Garcia et al found that patients with mild to moderate AD had a significant decrease in visual acuity, with respect to the age-matched controls.3 Patients with mild to moderate AD also had decreased contrast sensitivity, impaired oculomotor function, and abnormal viewing behavior.^1,3,4

The decreased outcomes in the psychophysical tests for patients with AD signal the changes in the layers of the retina. Using OCT, the first changes to be detected in patients with AD involve the central macula, with a decrease in central retinal thickness, which is a consequence of the degeneration of the inner layers of the retina.³

Researchers found that there was significant thinning to the RNFL, inner plexiform layer (IPL), and GCL in patients with mild AD, as well as slight thickening of both the inner and outer nuclear layers. Thinning of the retina was associated with cognitive decline, as it has also been linked to hippocampal atrophy.9 This suggests a connection between brain and retinal health, highlighting the importance of considering both diagnosis and treatment.

Retinal changes in AD

The hallmark of AD, Aβ plaques, has been well documented in the cerebral pathology, but it was not until recently that it was also noted in postmortem retinas of patients with AD and early-stage cases. Retinal plaque pathology reflects amyloid 4.7-fold increase of plaque burden in the retina of patients with AD, correlating with Aβ burden in the respective brains.⁵

Another OCT finding in AD is the degeneration of melanopsin-containing RGCs (mRGCs), which are photoreceptors known to facilitate the circadian rhythm. In a 2016 study, researchers found that the degeneration of mRGCs was associated with the retinal Aβ deposits in patients with AD.⁵ This is consistent with what we know to be true about AD and circadian rhythm dysfunction.

Studies have demonstrated GCL loss and thinning of the RNFL, particularly in the superior and inferior quadrants. There are significant vascular-related changes seen with RNFL thinning, including narrowed veins, reduction of blood flow, elevated blood oxygen saturation, and increased tortuosity.^6,7 Interestingly, the RNFL thinning and vascular changes do correlate with the visual dysfunction seen in AD. Although further investigation is required, Polo et al demonstrated a strong correlation between spectral domain OCT measurements, contrast-sensitive vision (CSV), and color vision (CV).⁸

In addition to superior quadrant RNFL thinning, CSV significantly worsened compared with healthy controls. In another study by Ferrari et al, the GCL thickness measurements correlated with the Mini Mental Status Examination scores.7 In another research group, inferior quadrant RNFL thickness was also found to be inversely associated with episodic memory scores, which is promising for OCT to be used to monitor visual and cognitive decline in AD.^6,9

Clinical applications

As the retina is a projection of the central nervous system, OCT may be a noninvasive way to access brain pathology and confirm a diagnosis of neurodegenerative disease.³ Limitations for using OCT to assess for the presence and progression of AD include a lack of specificity, limited understanding of the relationship between retinal changes in OCT and AD pathology, and the variability of retinal measurements. Although OCT can detect changes in retinal thickness, these alterations may not be exclusive to AD and can be seen in other neurodegenerative conditions or even normal aging. Furthermore, variability in retinal measurements can be influenced by other factors, such as ocular diseases and systemic conditions, posing challenges in interpreting OCT results accurately.

Although OCT has shown promise in detecting changes in the retina possibly linked to AD, further evaluation is required to determine what constitutes clinically significant findings in OCT scans concerning AD.

Conclusion

Because the brain and the retina share a common embryological origin, it makes sense that pathological changes in the brain would be reflected in the retina. Studies have supported this idea, prompting researchers to use OCT as a high-resolution, noninvasive imaging tool to observe retinal changes and potentially diagnose patients with AD.

There is a strong correlation between AD and retinal thinning, particularly of the RNFL in the superior and inferior quadrants, consistent with visual and cognitive dysfunctions.⁷ Furthermore, degeneration of mRGCs associated with retinal Aβ deposits aligns with the circadian dysfunction seen in patients with AD. However, further investigation with larger, more heterogeneous populations is required. Although OCT has shown promise in early diagnosis and monitoring of AD progression, there is an overlap of OCT findings in AD and other neurodegenerative diseases, presenting a challenge in differential diagnosis that future studies must address.

References

1. Guo L, Duggan J, Cordeiro MF. Alzheimer’s disease and retinal neurodegeneration. Curr Alzheimer Res. 2010;7(1):3-14. doi:10.2174/156720510790274491

2. 2022 Alzheimer’s disease facts and figures. Alzheimers Dement. 2022;18(4):700-789. doi:10.1002/alz.12638

3. Salobrar-García E, de Hoz R, Ramírez AI, et al. Changes in visual function and retinal structure in the progression of Alzheimer’s disease. PLoS One. 2019;14(8):e0220535. doi:10.1371/journal.pone.0220535

4. Molitor RJ, Ko PC, Ally BA. Eye movements in Alzheimer’s disease. J Alzheimers Dis. 2015;44(1):1-12. doi:10.3233/JAD-141173

5. La Morgia C, Ross-Cisneros FN, Koronyo Y, et al. Melanopsin retinal ganglion cell loss in Alzheimer disease. Ann Neurol. 2016;79(1):90-109. doi:10.1002/ana.24548

6. Maldonado RS, Mettu P, El-Dairi M, Bhatti MT. The application of optical coherence tomography in neurologic diseases. Neurol Clin Pract. 2015;5(5):460-469. doi:10.1212/CPJ.0000000000000187

7. Kromer R, Serbecic N, Hausner L, Froelich L, Aboul-Enein F, Beutelspacher SC. Detection of retinal nerve fiber layer defects in Alzheimer’s disease using SD-OCT. Front Psychiatry. 2014;5:22. doi:10.3389/fpsyt.2014.00022

8. Mendez MF, Tomsak RL, Remler B. Disorders of the visual system in Alzheimer’s disease. J Clin Neuroophthalmol. 1990;10(1):62-69.

9. Chen S, Zhang D, Zheng H, et al. The association between retina thinning and hippocampal atrophy in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review. Front Aging Neurosci. 2023;15:1232941. doi:10.3389/fnagi.2023.1232941