Ocular changes as potential biomarkers for early diagnosis of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. AD diagnosis often involves a thorough assessment, including clinical evaluation, cognitive testing, medical history examination, genetic testing, and biomarker analysis. Currently, the invasive nature and high costs of biomarker testing, such as cerebrospinal fluid analysis and neuroimaging, have limited the early detection and intervention of the disease. Therefore, researchers have explored cheaper and less invasive options, such as ocular imaging. This review discusses the close relationship between the eye and the central nervous system and ocular changes as a potential non-invasive AD biomarker. Ocular changes in AD have frequently been reported in the literature, particularly in the later stages of the disease. However, identifying biomarkers specifically attributable to AD remains a challenge. Additionally, this review provides a comprehensive overview of existing studies and highlights potential pathways for enhancing AD detection through ocular structural and functional evaluation. HIGHLIGHTS: Widespread screening for early detection of Alzheimer's disease (AD) is limited by cost and time constraints with current methods. Non-invasive and inexpensive methods are needed to overcome these difficulties. The eye is readily accessible and has shared developmental origins, neurobiology, and neurochemistry with the brain. The expanding field of ocular biomarker studies needs larger, well-characterized cohorts and longitudinal studies to understand the ocular changes for preclinical AD screening. Standards should be established for more methodical investigative approaches to identify ocular biomarkers that are specifically attributable to AD.

Keywords: Alzheimer's disease; amyloid beta; biomarkers; brain; early detection; ocular; retina.

FIGURE 1

AD biomarkers of the eye. Various ocular biomarkers have demonstrated changes in many cohorts. Ocular imaging has shown changes in pupillary response, corneal nerve morphometry, retinal structure, blood vessels, and ONH parameters. These findings support the potential of using the eye as a non‐invasive biomarker site for AD screening or diagnosis. +ve, positive; ˗ve, negative; AD, Alzheimer's disease; APOE, apolipoprotein E; Aβ, amyloid beta; CSF, cerebrospinal fluid; FAZ, foveal avascular zone; HC, healthy control; MCI, mild cognitive impairment; ONH, optic nerve head.

FIGURE 2

Current in vivo retinal imaging modalities and their findings on various cohorts. Color fundus and OCT imaging are the most established modalities, while SLO and hyperspectral imaging, which can provide higher resolution and spectral information, respectively, are still being developed. +ve, positive; Aβ, amyloid beta; AD, Alzheimer's disease; APOE, apolipoprotein E; CSF, cerebrospinal fluid; MCI, mild cognitive impairment; OCT/A, optical coherence tomography and optical coherence tomography angiography; ONH, optic nerve head; SLO, scanning laser ophthalmoscope.

FIGURE 3

Observed retinal pathologies in AD and MCI patients at different layers of the retina. The figure presents a schematic representation of pathological alterations across the various retinal cell layers associated with AD. Aβ plaques and fibrillar Aβ deposits are identified throughout the retinal layers, including the retinal RNFL, GCL,, , , , , IPL,, , , INL,, , , , OPL, ONL, ELM, and RPE. Tau deposition, in the form of different isoforms and neurofibrillary tangles, is frequently observed in the RNFL,, GCL,, , , IPL,, , , , , , INL,, , , , OPL,, , , , , and ONL. Neurodegeneration is primarily detected deeper in the retina, particularly in the GCL, INL, and ONL. Additionally, inflammatory responses such as microgliosis have been reported in the GCL, IPL, INL, and OPL,, whereas astrogliosis is typically observed in the GCL, IPL, and OPL. Aβ, amyloid beta; AD, Alzheimer's disease; ELM, external limiting membrane; GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; MCI, mild cognitive impairment; ONL, outer nuclear layer; OPL, outer plexiform layer; RNFL, retinal nerve fiber layer; RPE, retinal pigment epithelium.