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Retinal Nerve Fiber Layer Thickness In Alzheimer’s Disease

Retinal Nerve Fiber Layer Thickness In Alzheimer’s Disease

Worldwide, nearly 50 million people live with Alzheimer’s or related dementia according to Alzheimer’s Disease International (ADI). If breakthroughs are not discovered, this population could triple to 152 million by the year 2050. Alzheimer’s disease (AD) accounts for around two-thirds of all dementia diagnoses. Escalating costs and very limited treatment options make AD a scary thought for the patient, but it is very important for patients to see the physician earlier, rather than later. The classical AD diagnostic approaches – neuroimaging, patient interview, and blood tests – are suboptimal.

The pathology of AD may evolve in the brain about 10-15 years before clinical dementia presents. Dementia due to AD is, in fact, the final stage where symptom severity is escalated. Thus, researchers and clinicians focus on diagnosing AD in the early stage of mild cognitive impairment (MCI). MCI straddles age‐related forgetfulness and dementia. Although not all cases of MCI progress to dementia, roughly 10 to 15 percent of individuals with MCI may develop dementia or AD each year.

To improve the accuracy of in-vivo diagnosis, several biomarkers have been validated and are being used in clinical settings.

  • Magnetic resonance imaging (MRI): detects atrophy of the medial temporal lobe (MTL) within the cerebral cortex.

  • Positron Emission Tomography (PET) scan: amyloid-PET scan to detect amyloid β-protein (Aβ) deposition and FDG-PET scan to detect fluorodeoxyglucose (FDG).

  • Cerebrospinal fluid analysis (CSA): Measures tau protein and Aβ peptide levels.

These markers are greatly limited by high cost, invasiveness, and inter-and intra-laboratory variation between the clinical facilities performing the same diagnostic procedures. Furthermore, a lack of specific markers of disease stage also limits early AD diagnosis.

Alzheimer’s and the eye-brain connection

It is well known that Alzheimer’s strikes first in the entorhinal cortex (EC) followed by the hippocampal complex. AD can also affect the eye, particularly the retina, resulting in loss of visual acuity (VA), impaired vision and visual fields, defects in eye movement, and poor visual functions such as reading.

Embryologically, both the brain and retina have a similar origin and consist of neurons and glial cells responsible for cognition. AD-related changes in the retina include axonal degeneration of the optic nerve, reduction of retinal nerve fiber layer (RNFL) thickness, retinal vascular narrowing, and an increase in optic nerve cupping. Therefore, due to this eye-brain connection, it is reasonable to look for ocular markers to diagnose AD. Consequently, ocular markers provide an opportunity to use a minimally invasive method in diagnosing Alzheimer’s – through the medium of the eye.

Optical coherence tomography (OCT)

Optical coherence tomography (OCT), a novel transpupillary technique, is used to quantify RNFL thickness in-vivo. OCT works similarly to ultrasound, except that it uses low‐coherence light waves instead of high-frequency sound waves. The light waves are used to take high-resolution cross-sectional retinal scans. As OCT allows for visualization of the inner retinal layers, Retinal Ganglion Cell (RGC) and RNFL, their thickness can be mapped and measured effectively. Non-invasive and relatively inexpensive OCT has already been considered the standard imaging technique in neuro-ophthalmologic examinations.

As a promising tool to measure neurodegeneration, changes in the OCT measurements of the retinal layers can serve as a surrogate marker for the normal functioning of axons. Thus, OCT could become an invaluable tool for measuring axonal degeneration, as a marker, in different neurological conditions such as multiple sclerosis, optic neuropathy, and Parkinson’s disease.

Evidence of RNFL thinning in Alzheimer’s Disease

The retinal nerve fiber layer (RNFL) is composed of retinal ganglion cell axons, which form the optic nerve when bundled together. RNFL thins with aging, and the decreased thickness indicates retrograde degeneration of the retinal ganglion cell axons. There is also speculation that amyloid-β plaque deposits lead to neuroretinal atrophy.

Notably, some studies have reported a significant reduction in RNFL thickness in AD patients greater than is normal for their age group. In this context, Hinton et al. in 1986 showed histopathological evidence of axonal degeneration of the optic nerve and thinning of retinal (RNFL) in AD patients. Since then, several follow-up studies have revealed many different ocular biomarkers of Alzheimer’s disease.

Ascaso et al. concluded that all peripapillary quadrants, except the nasal quadrant, are significantly thinner in MCI patients in comparison to the healthy controls. Similarly, Liu et al. reported thinning of superior retinal quadrants, whereas Gao et al. found significantly thinner temporal quadrants and a reduced macular volume in Alzheimer’s and MCI patients. However, they failed to find a significant correlation between these neurological changes and the severity of the disease.

Results from the meta-analysis of OCT studies by Coppola et al. in MCI patients supported decay of peripapillary RNFL and a decline in macular thickness. Studies by Paquet et al. also reported a statistically significant reduction of RNFL thickness in patients with MCI compared to controls.

A study conducted by Carazo-Barrios L. et al. reported a significant linear trend towards RNFL thinning in the superior and temporal retinal quadrants of patients with AD and MCI. They also found a linear trend towards the nasal quadrant thickening as the cognitive impairment progressed. This is in contrast to the previous MCI studies that documented the thinning of nasal quadrants.

Hypotheses explaining RNFL thinning in AD

There have been several hypotheses proposed for the RNFL thinning in Alzheimer’s. The most important ones are:

1. Retina and AD pathology

It is proposed that AD pathology might develop in both the cortex and the ganglion cell layer of the retina. Löffler et al. found increased immunoreactivity of amyloid precursor protein in the eyes of elderly and in retinal pigment epithelium (RPE) cells in retinitis pigmentosa (RP) and age-related macular degeneration. However, a further study by Hinton et al. reported neither neurofibrillary degeneration nor amyloid angiopathy in the retina of test subjects with Alzheimer’s. The levels of Glial Fibrillary Acidic Protein (GFAP) in astrocytes are increased in AD eyes; as concluded by Blanks et al. The extensive retinal degeneration and neuron loss observed in AD retina provided further support for the role of the retina in Alzheimer’s.

2. Glaucoma and AD 

Several studies have shown significant similarities between glaucoma and AD pathology. Similar to AD, glaucoma is characterized by progressive degeneration of RNFL and resulting vision impairment. A study published in the Journal of European Neurology revealed a high occurrence rate of glaucoma in AD patients. The same study also concluded that glaucoma in Alzheimer’s patients tends to be more progressive than glaucoma in healthy controls.

3. Retrograde trans-synaptic degeneration and AD

Retrograde trans-synaptic degeneration could be the partial reason for retinal ganglion cell (RGC) loss in Alzheimer’s Disease.


There’s increasing evidence of RNFL thinning in Alzheimer’s patients but the relationship between the degree of cognitive decline and RNFL loss has not been established yet.

As demonstrated by various studies, measurement of RNFL thickness could become an important step in the early diagnosis of AD. However, further investigations are required to understand AD pathology as the neurodegenerative effects vary among patients depending on the severity of the diseases and different AD subtypes.





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