Advances in the development of new biomarkers for Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a complex, heterogeneous, progressive disease and is the most common type of neurodegenerative dementia. The prevalence of AD is expected to increase as the population ages, placing an additional burden on national healthcare systems. There is a large need for new diagnostic tests that can detect AD at an early stage with high specificity at relatively low cost. The development of modern analytical diagnostic tools has made it possible to determine several biomarkers of AD with high specificity, including pathogenic proteins, markers of synaptic dysfunction, and markers of inflammation in the blood. There is a considerable potential in using microRNA (miRNA) as markers of AD, and diagnostic studies based on miRNA panels suggest that AD could potentially be determined with high accuracy for individual patients. Studies of the retina with improved methods of visualization of the fundus are also showing promising results for the potential diagnosis of the disease. This review focuses on the recent developments of blood, plasma, and ocular biomarkers for the diagnosis of AD.

Keywords: Alzheimer's disease; Amyloid beta peptides; Biomarkers; Blood; Cytokines; Inflammation; MicroRNA; Ocular biomarkers.

Fig. 1

Classification of AD biomarkers. AD pathogenic proteins include the markers of the "amyloid theory", amyloid-beta (Aβ)₄₀ and Aβ₄₂, as well as markers of AD-related metabolic disorders, P-Tau (phosphorylated) and T-Tau (total). Biomarkers obtained by lumbar puncture are cerebrospinal fluid (CSF) biomarkers, CSF Aβ_1-42, CSF P-Tau, CSF T-Tau, and Neurogranin. Neurodegeneration markers include neurogranin and neurofilament light (NFL). The markers of inflammation include IL-1β and two soluble receptors sIL-1R1 and sIL-1R3, IL-8, SDF-1, intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion protein 1 (VCAM-1), progranulin, IL-33, and soluble interleukin 1 receptor-like (sST2). Many miRNAs are either up-regulated or down-regulated in studies on AD. The retina of the eye, as well as blood and plasma are being analyzed by a range of tools including single-molecular mass analysis (SIMOA), immunoprecipitation-mass spectrometry (IP-MS), immunomagnetic recovery (IMR), enzyme-linked immunosorbent assay (ELISA), and electrochemiluminescence immunoassays (ECL). Quantitative reverse transcription polymerase chain reaction (RT-qPCR) is used to identify miRNAs. The study of retinal degenerative changes, including ganglion cells and internal plexiform layers (GCIPL) and retinal nerve fiber layer (RNFL; p indicates peripapillary), is performed by optical coherence tomography (OCT) and spectral domain optical coherence tomography (SD-OCT)

Fig. 2

The effect of miRNAs on the pathology of AD. This image visualizes the effect of dysregulated miRNAs on neuronal degeneration. MiRNAs have an effect on the disruption of the cell cycle, regulation of Aβ metabolism, regulation of Tau-protein metabolism, and neuroinflammation

Fig. 3

Association of AD pathways with miRNAs with potential for diagnostic applications. As one of the key pathological pathways of AD development, Aβ has effects on the development of mitochondrial dysfunction, oxidative stress, and induction of the calcium signaling pathway. The calcium signaling pathway affects the development of apoptosis via lipid oxidation, protein oxidation, and DNA damage, leading to cell death. One of the mechanisms of neuronal damage is represented by hyperphosphorylated Tau protein, which causes neurofibrillary degeneration. The image also shows the effect of inflammatory factors on neuronal damage. TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor; IKK, IκB kinase; PKR, protein kinase R; JNK, c-Jun N-terminal kinase; RAGE, receptor for advanced glycation endproducts; MEK, mitogen-activated protein kinase; ERK1/2, extracellular signal-regulated kinases; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IL, interleukin; mTOR, mechanistic target of rapamycin; VDCC, voltage-dependent calcium channel; Cdk5, cyclin dependent kinase 5; PP2B, protein phosphatase-2B; GSK3B, glycogen synthase kinase 3 beta; NMDAR, N-methyl-D-aspartate receptor; NOS, nitric oxide synthase; RyR, ryanodine receptors; PSEN, presenilin; SERCA, sarco/endoplasmic reticulum Ca2+-ATPase; FADD, Fas-associated protein with death domain; BID, BH3 interacting-domain death agonist; CytC, cytochrome complex; APP, amyloid precursor protein; APP-BP1, amyloid precursor protein-binding protein 1; BACE1, beta-site APP cleaving enzyme 1; Cx proteins I-V, electron transport chain enzymes (complexes I-IV) and the ATP synthase (complex V); ABAD, amyloid beta-binding alcohol dehydrogenase; CypD, mitochondrial peptidyl-prolyl cis–trans isomerase D