Potential Retinal Biomarkers in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) represents a major diagnostic challenge, as early detection is crucial for effective intervention. This review examines the diagnostic challenges facing current AD evaluations and explores the emerging field of retinal alterations as early indicators. Recognizing the potential of the retina as a noninvasive window to the brain, we emphasize the importance of identifying retinal biomarkers in the early stages of AD. However, the examination of AD is not without its challenges, as the similarities shared with other retinal diseases introduce complexity in the search for AD-specific markers. In this review, we address the relevance of using the retina for the early diagnosis of AD and the complex challenges associated with the search for AD-specific retinal biomarkers. We provide a comprehensive overview of the current landscape and highlight avenues for progress in AD diagnosis by retinal examination.

Keywords: Alzheimer’s disease; metabolism; mitochondria; ocular biomarkers; retinal alterations.

Figure 1

Visual changes in Alzheimer’s disease and erase AD. Several clinical and functional alterations have been reported in Alzheimer’s disease patients, such as decreased pupillary light reflex, increased pupil size, and increased excavation of the optic nerve. Other features include decreased contrast sensitivity, decreased visual acuity, stereopsis, abnormal hypometric saccade, and reduced visual sensitivity, among other alterations.

Figure 2

Interaction between Müller glia and microglia. Signals from Müller glia induce changes in microglia, causing them to either rest or become activated: (1) Activated microglia: Once activated, Müller glia activate microglia by CCL2 and CCL3 secretion. (2) Neuroinflammation: Microglia in turn produce IL-1β, IL-6, and iNOS in a positive feedback loop. This results in unregulated over-activation leading to neurodegeneration. (3) Resting microglia: ATP secretion through Müller glial pannexin channels allows microglia to rest. CCL Chemokine (C-C motif) ligand. IL Interleukin. iNOS Inducible nitric oxide synthase. ATP Adenosine triphosphate.

Figure 3

Morphology in the healthy neuron and the neuron of Alzheimer’s disease. In Alzheimer’s disease the neuron changes morphology, the dendrites are shorter, the axon is reduced decreasing the synapse, and the mitochondria become dysfunctional due to the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles, leading to an increase of reactive oxygen species (ROS), and subsequent cell death.

Figure 4

Healthy and dysfunctional mitochondria in the retina. The RPE/photoreceptor complex resides in a highly oxidative environment. A large number of mitochondria are located in the outer end of Müller glia, in the inner segments of photoreceptors, and in the basal part of RPE cells. The retina is a highly energy demanding organ. In healthy retinal cells, glycolysis occurs in the cytoplasm, providing pyruvate and lactate to the mitochondria where they can be substrates for acetyl-CoA synthesis, fueling the TCA cycle and electron transport chain (complex I–V) activity with final energy production in the form of ATP. In the Alzheimer’s disease retina, glycolysis is affected by the amyloid-β (Aβ) peptide causing the increase in reactive oxidative species (ROS), while hyperphosphorylated tau (pTau) inhibits the electron transport chain, provoking the increase of ROS inside the matrix of the mitochondria. In a harmful cycle, the increase in ROS causes mutations in mitochondrial DNA that will produce defective proteins which in turn decreases ATP and increases ROS with the subsequent oxidative stress, mitochondrial damage, and apoptosis which contribute to the retinal pathology of AD. RGC Retinal ganglion cells. AC Amacrine cells. BC Bipolar cells. MC Müller cells. HC Horizontal cells. PR Photoreceptors. RPE Retinal pigmented epithelium. I NADH reductase. II Succinate dehydrogenase. III Cytochrome complex. IV Cytochrome C oxidase. V ATP synthase. TCA cycle Tricarboxylic acid cycle. MCT Monocarboxylate transporter. ROS Reactive oxygen species. mtDNA Human mitochondrial DNA. ATP Adenosine triphosphate. ADP Adenosine diphosphate.

Figure 5

Non-invasive imaging of the retina in Alzheimer’s disease. In Alzheimer’s disease patients there are visual alterations that can lead us to Alzheimer’s disease diagnosis using technological tools such as optical coherence tomography (OCT), optical coherence tomography angiography (OCTA), fundus photography, and hyperspectral imaging.