Varun Ranganathan, MC Optom

Clinical Optometrist

An OCULAR Interface Exclusive

Keywords: Alzheimer’s Disease, Ophthalmology, Optometry, Biomarkers, Artificial Intelligence

Synopsis: Alzheimer’s Disease (AD) is a common and devastating neurodegenerative condition affecting the elderly. Early detection of this condition is key in managing the symptoms effectively. Our eyes can provide easy access on subtle cues about our systemic health and being able to detect these biomarkers with the help of Artificial Intelligence has never been more important.

Alois Alzheimer – German Psychiatrist

Alzheimer’s Disease (AD) is a neurogenerative condition progressive impairment of behavioral and cognitive functions including memory, comprehension, language, attention, reasoning, and judgment. It is the most common form of dementia usually affecting people aged 65 and older and is charaterised by neuronal cell death in the brain ¹.

Pathophysiology:

The pathophysiology of Alzheimer’s is characterised by the accumulation of abnormal neuritic plaques and neurofibrillary tangles ². These plaques are called beta amyloid plaques (Aβ) which is a derivative of amyloid precursor protein (APP) which is a naturally occurring protein ³. Abnormal levels of this protein accumulate between neurons disrupting communication. A naturally occurring protein called tau is responsible is stabilising axonal microtubules and helping in guiding nutrients along axons. Abnormal levels of tau aggregate inside the neurons to form a twisted structure called neurofibrillary tangles ⁴. It is to be noted that tangles are correlated more to Alzheimer’s than plaques, but plaques are easily observable than tangles.

Detecting Biomarkers in The Eye

Beyond the brain, the human eye can be used to detect early signs of AD because it has a direct connection to the brain and the biomarkers can be detected through more than one of the eye’s structures and the most promising ones are tears, cornea, and retina.

In human tears there is an increased levels of tau and Aβ in patients with AD and a study developed an inexpensive and disposable biosensor that could detect Aβ in tears ⁵.

The use of corneal confocal microscopy (CCM) is particularly useful in assessing corneal nerve health. AD, being a neurodegenerative condition, has been shown to affect corneal nerve fibre density, length, branching and the dendritic cells ⁶. Dehghani et al., also found the levels of acetylcholine to be reduced in patients with AD, which plays a key role in development and maintenance of corneal epithelium ⁷.

In screening for AD, retina is a viable target because it shares similar embryonic structure and origin to the brain ⁸. Koronyo-Hamaoui et al., found a correlation between AD progression and severity/volume of Aβ but in the retina of mice ⁹. The presence of Aβ plaques in retina offers high specificity to the diagnosis of AD. In a more recent study conducted on live humans, curcumin dye which is naturally found in turmeric, were given to subjects a week earlier and retinal segments were imaged using scanning laser ophthalmoscope non-invasively ¹⁰. Curcumin binds to Aβ plaques in retina readily and has natural autofluorescence properties making the detection of these plaques easy ¹¹.

Artificial Intelligence (AI) Potential in Eye Tests

AI algorithms are increasingly used in accordance with ophthalmological machines like Optical Coherence Tomography (OCT) to diagnose conditions much earlier on. With AI carving a niche for itself in eye care, Optometrists acting as gatekeepers are placed perfectly in primary care setting to detect AD. By leveraging the power of AI algorithms, a routine eye examination can become lifesaving.

References:

1. Tang Y, Lutz MW, Xing Y. A systems-based model of Alzheimer’s disease. Alzheimers Dement. 2019 Jan;15(1):168-171.
2. Kumar A, Sidhu J, Goyal A, et al. Alzheimer Disease. [Updated 2022 Jun 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499922/
3. What Happens to the Brain in Alzheimer’s Disease? | National Institute on Aging (nih.gov)
4. Hart de Ruyter FJ, Morrema THJ, den Haan J; Netherlands Brain Bank; Twisk JWR, de Boer JF, Scheltens P, Boon BDC, Thal DR, Rozemuller AJ, Verbraak FD, Bouwman FH, Hoozemans JJM. Phosphorylated tau in the retina correlates with tau pathology in the brain in Alzheimer’s disease and primary tauopathies. Acta Neuropathol. 2023 Feb;145(2):197-218. doi: 10.1007/s00401-022-02525-1. Epub 2022 Dec 8. Erratum in: Acta Neuropathol. 2022 Dec 23;: PMID: 36480077.
5. Wang Y.-R., Chuang H.-C., Tripathi A., Wang Y.-L., Ko M.-L., Chuang C.-C., et al. (2021). High-Sensitivity and Trace-Amount Specimen Electrochemical Sensors for Exploring the Levels of β-Amyloid in Human Blood and Tears. Anal. Chem. 93 8099–8106. 10.1021/acs.analchem.0c04980.
6. Ponirakis G., Al Hamad H., Sankaranarayanan A., Khan A., Chandran M., Ramadan M., et al. (2019). Association of corneal nerve fiber measures cognitive function in dementia. Ann. Clin. Transl. Neurol. 6 689–697. 10.1002/acn3.746.
7. Dehghani C., Frost S., Jayasena R., Fowler C., Masters C. L., Kanagasingam Y., et al. (2020). Morphometric Changes to Corneal Dendritic Cells in Individuals With Mild Cognitive Impairment. Front. Neurosci. 14:556137. 10.3389/fnins.2020.556137.
8. Erskine L, Herrera E. Connecting the Retina to the Brain. ASN Neuro. 2014;6(6). doi:10.1177/1759091414562107.
9. Koronyo-Hamaoui M., Koronyo Y., Ljubimov A. V., Miller C. A., Ko M. H. K., Black K. L., et al. (2011). Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model. Neuroimage 54(Suppl. 1), S204–S217.
10. Koronyo Y, Biggs D, Barron E, Boyer DS, Pearlman JA, Au WJ, Kile SJ, Blanco A, Fuchs DT, Ashfaq A, Frautschy S, Cole GM, Miller CA, Hinton DR, Verdooner SR, Black KL, Koronyo-Hamaoui M. Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease. JCI Insight. 2017 Aug 17;2(16):e93621. doi: 10.1172/jci.insight.93621. PMID: 28814675; PMCID: PMC5621887.