Liquid Biomarkers for Early Diagnosis of Alzheimer's disease
Bogolepova AN, Makhnovich EV, Kovalenko EA and Osinovskaya NA
Published on: 2022-12-21
One of the most significant tasks of modern neurology is the study of dementia problems. According to the general opinion of researchers, the most common cause of dementia among people over 65 years of age is Alzheimer's disease (AD). This disease causes at least 60-70% of dementias. Diagnosis of Alzheimer's disease in the early stages is difficult, since the symptoms of the disease are nonspecific, and can be noted in other neurodegenerative, as well as vascular diseases of the brain. In this regard, a special role in the lifetime diagnosis of Alzheimer's disease is played by modern research methods, such as positron emission tomography (PET) and the determination of biomarkers of cerebrospinal fluid (Aß and tau). However, it should be noted that all of the above methods are expensive and invasive. Therefore, an urgent direction is the search for new biomarkers of Alzheimer's disease that have a low cost and are used in routine clinical practice. Currently, these include biomarkers of Alzheimer's disease, determined in biological fluids – saliva and blood (Aß and tau protein). Also recently, much attention has been paid in the scientific literature to the role of sirtuin proteins (SIRT) in the development of neurodegenerative diseases. Published data indicate that SIRT regulates many fundamental biological processes in the body, including processes that are disrupted in AD, such as Aß precursor processing, neuroinflammation, neurodegeneration and mitochondrial dysfunction. This makes it possible to identify SIRT as potential biomarkers of AD, the presence of which can be determined in biological fluids, such as saliva and blood.
KeywordsAlzheimer's disease; amyloid-? (A?); tau protein (tau); sirtuins; biomarkers
One of the most important problems of modern medicine is the existence of neurodegenerative diseases, which are actively progressing every year and have a clear tendency to increase the number of cases.The most common disease of this type is Alzheimer's disease (AD). AD is one of the most common neurodegenerative diseases, which, according to statistics, is the cause of 60-70% of cases of dementia . This is a degenerative disease, manifested in the deterioration of a person's cognitive abilities (memory, speech, etc.) . Diagnosis of AD is most often possible only at the stages of pronounced clinical manifestations.
Quite often, for older and elderly patients, mnestic disorders are regarded as a natural aging process, which is due to the physiological processes of normal aging due to a decrease in brain volume. However, memory impairment may be a consequence of pathological changes in the brain, which is based on the neurodegenerative process. In this regard, patients with AD seek help in the later stages of the disease. The diagnosis of AD is established by doctors on the basis of symptoms and signs of brain atrophy using magnetic resonance imaging (MRI) or computed tomography (CT) [3,4]. However, these methods may not always be safe, and at the same time they are not available. The key link in the diagnosis of AD is neuropsychological testing, however, during neuropsychological testing, a significant number of cases of AD at the pre-dement stage remain undiagnosed, since the neuropsychological tests used have low sensitivity, but high specificity . In view of the above factors, the attention of researchers is increasingly focused on the development of laboratory diagnostic methods, which include the detection of biological markers with which it is possible to determine the risk of developing AD at an early stage. The aim of this study is to summarize and discuss potential biomarkers of AD, especially liquid biomarkers.
Biomarkers Of AD
It is well known that pathological changes in AD appear several years, if not decades, before the patient has obvious clinical signs and will be diagnosed. Clinical symptoms are observed only 10-20 years after the onset of pathological changes in the brain, and the clinical stage of AD can last from 5 to 12 years. Several biomarkers have been proposed for early detection of AD: in cerebrospinal fluid (CSF) - a combination of amyloid-β of 42 amino acids (Aß42), total tau protein (t-tau), hyperphosphorylated tau protein (p-tau); Positron emission tomography (PET) data with 18F-fluorodeoxyglucose (18F-FDG), PET with amyloid marker Pittsburgh substance B (PiB), tau PET.
Determination of biomarkers in CSF is possible both at the preclinical and at the early clinical stage of AD. In AD, Aß42 accumulates in brain tissues, and its concentration in CSF decreases, which is combined with an increase in the level of t-tau in CSF and the appearance of its special form – p-tau . According to the literature, it is noted that the ratio Aβ42/Aβ40 in CSF has a higher efficiency for detecting AD than Aß42 in CSF as a separate biomarker. Many studies also show that the Aβ42/Aβ40 ratio in CSF is better consistent with positive results according to PET data with the amyloid marker PiB [6,7]. However, these research methods, due to their invasiveness and high cost, are still difficult to access for many patients. Therefore, the search for new biomarkers for early diagnosis of Alzheimer's disease is one of the important tasks of modern neurology and gerontology.
Aβ and P-Tau in Blood as Potential Biomarkers in AD
One of the significant directions in the diagnosis of AD was the search for potential biomarkers in the blood, as the most convenient for practical use in clinical practice. However, until 2016, the results of the Aβ study in blood plasma did not correlate sufficiently with a decrease in Aβ in CSF . Later, the methods of solid-phase enzyme immunoassay (ELISA) were methodically improved and an effective diagnostic indicator was revealed - the ratio Aß42/Aß40 in blood plasma in patients with AD . The Aβ42/Aβ40 ratio in plasma demonstrated sensitivity of 96.7%, specificity of 81.0% and accuracy of 90.2% of the total data. A high correlation was demonstrated by the Aß42/Aß40 ratio in plasma with the Aβ42/Aβ40 ratio in CSF (r = 0.785, p<0.0001) [10,11]. Studies have been conducted that have shown that a lower Aβ42/Aβ40 ratio in blood plasma correlates with a higher level of amyloid accumulation in the cerebral cortex [11-18], and also correlates with a more pronounced decrease in cognitive functions and with subsequent follow-up, the risk of developing dementia increases [20-25]. In 2020, a large cohort study was conducted in which the plasma Aβ42/Aβ40 ratio with the neocortical load ratio Aß was studied using a standardized PET absorption coefficient at three separate time points (month 18 (n = 176), month 36 (n = 169) and month 54 (n = 135)) in patients with BA and healthy individuals. According to the results of this study, it was revealed that the ratio of Aβ42/Aβ40 in plasma was significantly reduced in patients with AD and correlated with a positive result of PET with amyloid at all-time points (p < 0.0001) . Two studies have shown that a biomarker such as p-tau in serum and plasma can be used as a differential diagnostic indicator of dementia in patients with AD and frontotemporal dementia [27,28].
S. Palmqvist , in an article published in 2020, showed that p-tau217 in blood plasma makes it possible to distinguish clinically diagnosed AD from dementia of another etiology with the same accuracy as p-tau217 in CSF and PET tau (all with AUC > 0.95). At the same time, the level of p-tau217 in blood plasma has a 5-7-fold increase in dementia in patients with AD compared with other neurodegenerative diseases . Five studies were conducted that examined the relationship between changes in p-tau in blood plasma and postmortem data. All studies have confirmed that p-tau in blood plasma can differentiate AD with high accuracy from pathology unrelated to AD . P-tau in blood plasma at the baseline level is a significant predictor of the progression of cognitive decline and can be compared with p-tau in CSF. In a study by S. Janelidze , it was found that individuals with an altered baseline level of p-tau181 significantly increased the risk of developing dementia in AD in the future (HR = 10.9, 95%; CI = 5.0–24.0).
Interesting data were obtained by J. Lantero Rodriguez  that p-tau181 in blood plasma can be a predictor of the development of AD at least 8 years before neuropathological confirmation and correlates with the severity of changes according to tau PET data. There is a significant correlation of p-tau in blood plasma with other biomarkers in AD - Aβ and tau pathology in CSF and according to PET data. However, plasma p-tau and CSF. P-tau correlate only in the presence of Aβ pathology. Consequently, p-tau in plasma is sensitive to pathologies of both Aß and tau but begins to increase in response to Aβ change or simultaneously with it . Thus, plasma p-tau (p-tau181 and p-tau217) and Aβ (SAβ42/Aβ ratio) were selected as potential biomarkers for their direct use in the diagnosis of AD. While according to several studies, t-tau in blood plasma has shown limited validity as a biomarker of AD .
Sirtuin Proteins as Potential Biomarkers of AD
In addition to ensuring the silence of unnecessary genes in a certain tissue, the second function of SIRT is the ability to repair a damaged section of DNA, as a result of which gene expression may change with aging or DNA damage . The most important cellular processes such as genetic control, aging, cell survival, metabolism and DNA repair are carried out with the participation of SIRT. Age-related decrease in SIRT expression causes a variety of pathophysiological processes that can lead to neurodegeneration . Animal models have shown that SIRT1 plays a neuroprotective role in the brain. Autopsy material revealed a significant decrease in the level of SIRT1 expression in the parietal lobe of the brain in patients with AD compared with the control group. Accumulation of Aβ and tau in the cerebral cortex in patients with AD is closely associated with a decrease in SIRT1 expression . A growing body of evidence suggests that SIRT1 regulates many processes that are disrupted in AD, such as ARP processing, neuroinflammation, neurodegeneration, and mitochondrial dysfunction. SIRT1 weakens amyloidogenic processing of amyloid-β protein precursor (APP) in in vitro cell culture studies and in transgenic mouse models of Alzheimer's disease. SIRT1 increases the expression of the ADAM10 gene (a disintegrin and metalloproteinase domain) encoding α-secretase. Since α-secretase is the enzyme responsible for the non-amyloidogenic cleavage of ARP, the activation of α-secretase shifts the processing of ARP in order to reduce the pathological accumulation of suspected toxic Aβ species, which results from the activity of β-secretase and γ-secretase .
ApoE4 exacerbates the pathology associated with AD by increasing the amyloidogenic processing of the precursor of the amyloid protein-β (APP) and, consequently, the production of Aß; and by reducing the clearance of Aß mediated by astrocytes and microglia. ApoE4 expression is also associated with mitochondrial dysfunction and lysosomal leakage in AD. A decrease in SIRT1 as a result of ApoE4 expression may be the main cause of the harmful effects of ApoE4, as it may lead to a decrease in FOXO3-mediated antioxidant response, PGC1a-mediated sequestration of radical oxygen species (ROS) and ADAM10 expression. A decrease in SIRT1 also increases p53-mediated apoptosis, NFkB-mediated Aß toxicity, and tau acetylation; all of which exacerbate the pathology of AD . It should be noted that several proteins play an important role in energy metabolism, in particular, the key mitochondrial nicotinamide adenine dinucleotide (NAD) The +-dependent protein is SIRT3, which models the production of adenosine triphosphate (ATP) [44,45]. Numerous studies demonstrate that energy metabolism is closely related to human cognitive functions, in particular, cerebral hypometabolism is interrelated with CN in AD [46-48]. In addition, hypometabolism is associated with memory impairment, it is also considered a predictor of a decrease in many other cognitive functions. There is an inverse relationship between Aß deposition and glucose metabolism . At preclinical stages, hypometabolism serves as an accurate predictor of cognitive decline and characterizes AD [50,51].
Autopsy material of patients with AD revealed that the level of SIRT3 was reduced and correlated with the severity of cognitive deficits [52,53]. In a mouse model of AD, it was found that the SIRT3 agonist, β-hydroxybutyrate, blocked the penetration of amyloid protein into neurons and restored mitochondrial functions, which improved cognitive functions in mice with AD . These studies suggest that SIRT3 expression plays an important role in the pathogenesis of AD. In 2013, it was found that cells lacking SIRT6 are unable to repair various types of DNA damage. It is important to note that in mice with SIRT6 deficiency, DNA damage is detected in a tissue-specific manner, especially in the brain . Next, a brain-specific model of a SIRT6 knockout mouse was developed. Accelerated aging of the brain and accumulation of damaged DNA, as well as increased apoptosis and p-tau levels were revealed. Already by the age of 4 months, pronounced violations of behavioral tasks were demonstrated. With the depletion of SIRT6 in cells, an increase in the stability and phosphorylation of tau was noted. These data show that SIRT6 has a protective effect on the brain, protecting against natural DNA damage and, accordingly, neurodegeneration . Later it was revealed that the high expression of SIRT1, SIRT6 in the hippocampus is a protection factor against AD .
In 2020, a study was conducted in which the expression of SIRT1, SIRT3, SIRT5 and SIRT6 was evaluated on autopsy material of the hippocampus using immunohistological staining of sections and the concentration of signaling molecules in saliva was determined, which were measured by ELISA in volunteers without neurological pathology and in patients with AD. According to the results of the study, in patients with AD, the expression of SIRT1, SIRT3 and SIRT6 on autopsy material of the hippocampus and in saliva was reduced by 1.5–4.9 times compared with healthy individuals of the corresponding age. However, the most significant indicator was the expression of SIRT6 in immunohistochemical stained sections of the hippocampus in patients with AD and saliva, which was reduced by 2.5–4.5 times, compared with healthy volunteers of the same age .
In 2021, a study was conducted in which serum levels of all seven SIRT were evaluated by surface plasmon resonance in three groups: AD, MCI and geriatric control. In addition, the data was confirmed using Western blotting. Of the seven SIRTs, serum levels of SIRT1, SIRT3 and SIRT6 (mean + standard deviation) were significantly reduced in AD (1,65 ± 0,56, 3,15 ± 0,28, 3,36 ± 0,32 ng / m?l); in comparison with MCI (2,17 ± 0,39, 3,60 ± 0,51, 3,73 ± 0,48 ng / m?l) and geriatric control (2,84 ± 0,47, 4,55 ± 0,48, 4,65 ± 0,55 ng / m?l). The concentration decreased significantly with the progression of AD. ROC analysis showed that SIRT1, SIRT3 and SIRT6 in serum have greater accuracy in the diagnosis of AD .
Currently, it remains a priority to diagnose AD in the early stages of the disease - before clinical manifestation, as well as to identify the progression of the disease. Studies have shown that biomarkers with proven efficacy in the diagnosis of AD are the ratio Aβ42/Aβ40 and p-tau in CSF, as well as PET data with 18F-FDG, with PiB and tau PET. Despite this, these biomarkers are not used as often. Recently, the Aβ and p-tau biomarkers in the blood have been actively studied, since, unlike the above biomarkers, they have wider availability, lower cost and are safer with respect to the development of adverse events during the procedure. Of course, it is unlikely that blood biomarkers will surpass CSF biomarkers and will be used as the main diagnostic tool in AD. However, they can have great potential when used in combination with neuropsychological tests and routine MRI diagnostics at the screening stage. At the same time, an additional diagnostic biomarker confirming the presence of AD can be the determination of SIRT in both plasma and serum.
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