Rohan Gupta

Background: Alzheimer’s disease (AD) is a progressive, irreversible neurodegenerative disease and is the leading cause of dementia in individuals over 65.¹ The hallmarks of AD are extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tau (NFT). Typically, AD presents with a wide range of symptoms, which often begin as mild cognitive impairment (MCI) and may progress to more severe cognitive decline.² Diagnosis traditionally begins with the identification of this cognitive decline, followed by imaging and assessments, such as Aβ-PET.  However, postmortem studies have shown a ~30% rate of misdiagnosis; hence, postmortem histopathological analysis remains the gold standard for AD diagnosis.³ Developing methods for the early diagnosis of AD could lead to improved outcomes for patients. Studies indicate a gap of up to 20 years between the initial onset of Aβ accumulation and symptom onset.⁴ This lengthy progression, coupled with the potential of new therapies to slow the progression of the disease, underscores the critical need for early detection and screening. Recently, the retina has emerged as a particularly promising site for early AD screening and is often described as the “window to the brain” due to its shared embryological origin and its ability to mirror central nervous system health. Additionally, advances in retinal imaging have allowed for non-invasive, cost-effective, and accessible tools for evaluating retinal health. This systematic review aims to evaluate the potential of retinal biomarkers for early AD detection.

Methods: A PubMed search was conducted using the keywords: “retina”, “Alzheimer’s Disease”, early diagnosis”, “early detection”, “OCT”, and “OCTA” and focused on literature published since 2019.

Results: Four key results emerged from the review. First, proteomic analysis revealed significant changes in protein expression in transgenic mice retinas, identifying 17 consistently differentially expressed proteins as potential biomarkers for AD.⁵ Second, postmortem studies of human retinas demonstrated increased peripheral Aβ accumulation in the inner retina and were linked to cognitive deficits, confirming the retina as a site reflecting AD pathology.⁶ Third, optical coherence tomography (OCT) and OCT-angiography (OCTA) supported these findings, showing notable thinning of inner retinal layers and reduced vascular density in AD patients.^{2, 7} Fourth, hyperspectral imaging highlighted significant spectral deviations in retinal regions in higher-functioning MCI patients, emphasizing the potential of early detection.⁸

Conclusions: These findings demonstrate the promising role of retinal biomarkers in facilitating early AD detection. However, small sample sizes, inconsistent inclusion criteria, and dissimilar methodology of existing studies necessitate further research.

Works Cited:

1. Tahami Monfared AA, Byrnes MJ, White LA, Zhang Q. Alzheimer’s disease: epidemiology and clinical progression. Neurol Ther. 2022;11(2):553-569. doi:10.1007/s40120-022-00338-8
2. Yoon SP, Grewal DS, Thompson AC, et al. Retinal microvascular and neurodegenerative changes in Alzheimer’s disease and mild cognitive impairment compared with control participants. Ophthalmol Retina. 2019;3(6):489-499. doi:10.1016/j.oret.2019.02.002
3. Yuan A, Lee CS. Retinal biomarkers for Alzheimer’s Disease: the facts and the future. Asia Pac J Ophthalmol (Phila). 2022;11(2):140-148. doi:10.1097/APO.0000000000000505
4. Knopman DS, Amieva H, Petersen RC, et al. Alzheimer disease. Nat Rev Dis Primers. 2021;7(1):1-21. doi:10.1038/s41572-021-00269-y
5. Iqbal J, Zhang K, Jin N, et al. Alzheimer’s disease is responsible for progressive age-dependent differential expression of various protein cascades in retina of mice. ACS Chem Neurosci. 2019;10(5):2418-2433. doi:10.1021/acschemneuro.8b00710
6. Karonyo Y, Rentsendorj A, Mirzaei N, et al. Retinal pathological features and proteome signatures of Alzheimer’s disease. Acta Neuropathol. 2023; 145(5):409-438. doi:10.1007/s00401-023-02548-2
7. 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
8. More SS, Beach JM, McClelland C, Mokhtarzadeh A, Vince R. In vivo assessment of retinal biomarkers by hyperspectral imaging: early detection of Alzheimer’s disease. ACS Chem Neurosci. 2019;10(11):4492-4501. doi:10.1021/acschemneuro.9b00331