Peripheral Inflammatory Biomarkers of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease of unknown pathological origin. The clinical diagnosis of AD is time-consuming and needs to a combination of clinical evaluation, psychological testing, and imaging assessments. Biomarkers may be good indicators for the clinical diagnosis of AD; hence, it is important to identify suitable biomarkers for the diagnosis and treatment of AD. Peripheral inflammatory biomarkers have been the focus of research in recent years. This review summarizes the role of inflammatory biomarkers in the disease course of AD.

Keywords

Alzheimer’s disease biomarkers inflammatory neurodegeneration

Alzheimer’s disease (AD), the most common type of dementia, was first discovered and reported in 1906. The core pathological feature of AD is the presence of senile plaques composed of insoluble amyloid-β (Aβ) fibril deposits, activated microglia, astrocytes, and degenerating neurons. AD is no longer considered a single unified condition, but a complex syndrome. Early diagnosis and treatment of AD is challenging. It has been reported that Aβ may be deposited as early as 20 years before the onset of clinical symptoms [1]. Further, the pathogenesis of AD remains unclear. Finding suitable biomarkers is critical to addressing the clinical challenges of AD. To this end, new peripheral biomarkers have been extensively researched in the recent years. Some studies have proposed marker-based diagnostic tools for the diagnosis of early onset AD. The accuracy of some diagnostic models is very high, suggesting that biomarkers offer good prospects in diagnosing AD, highlighting the importance of incorporating biomarkers into the diagnostic framework [2 –4].

Inflammatory responses play a complex role in the pathogenesis of AD [5]. An increasing number of clinical trials continue to assess relevant neuroinflammatory biomarkers, with the aim of advancing the early diagnosis, treatment, and prognosis of AD. Given the availability, ease of use, and blood-compatibility of peripheral inflammatory biomarkers, this review aims to summarize some promising biomarkers to provide a direction for further research.

NEUROINFLAMMATION IN AD

In recent years, neuroinflammation has become a prominent aspect of AD research. Certain immune gene mutations, such as TREM2, CD33, CR1, and IL-8, are genetic risk factors for AD [6, 7]. Aggregation and proliferation of glial cells near senile plaques and neurofibrillary tangles are characteristic features observed in the brain of AD patients [8]. The senile plaque formed by the deposition of Aβ in the brain of patients with AD and the nerve fiber tangle (neurofibrillary tangles) formed by abnormal phosphorylation and aggregation of tau proteins are two important pathological features of AD. The activation of microglia and astrocytes and some inflammatory factors released by microglia and astrocytes in the brain of patients with AD are also involved in the pathological changes of tau protein, including, affecting their structure, function, distribution, and transmission.

The blood-brain barrier (BBB) has a protective effect on the brain. Historically, the central nervous system (CNS) was considered an immunoprivileged organ, as it lacked a lymphatic system and was shielded from the peripheral circulation by the BBB. However, it is now clear that the BBB can respond to soluble factors and plasma proteins and further communicate with peripheral immune system cells, thus establishing neuroimmune system interactions. These findings corroborate the view that neuroinflammation contributes to AD pathology [9, 10]. Therefore, the brain can no longer be considered an immunoprivileged organ. In the brains of patients with AD, an increased concentration of chemokines and cytokines may attract monocytes or macrophages in the peripheral circulation to cross the BBB to the CNS, further exacerbating the inflammatory response [11].

Chronic neuroinflammation can destroy the BBB, causing microglia, which are present in the CNS, to get activated and release pro-inflammatory cytokines. This cascade process further generates an immune response [10]. An excessive activation of this continuous pro-inflammatory response is associated with many neurodegenerative diseases such AD.

Inflammatory factors in the brain will enter the blood through the blood-cerebrospinal fluid barrier, and in the follow-up to promote the release of inflammatory factors from peripheral blood inflammatory cells as well [10, 11]. Peripheral inflammatory markers are known to more be derived from the secretions of peripheral immune system cells. Some studies have shown that the crosstalk between the peripheral immune system and the CNS inflammatory response may be part of the pathogenesis of some neurodegenerative diseases, so there may be dual activation of the peripheral immune system and CNS in AD, resulting in the imbalance of inflammatory markers secretion [12].

Astrogliosis is also a core feature of patients with AD [13]. Astrocytes can increase the production of cytokines and directly or indirectly affect the release of inflammatory signaling molecules through microglia [14]. It has been reported that the number of astrocytes decreased in early pathological stages of AD animal models (APP transgenic mice) [15]. Apolipoprotein E promotes the degradation of Aβ deposited by astrocytes [16]. In the initial pathological process of AD, activated microglia and astrocytes are beneficial in the clearance of Aβ. As the disease progresses, activated microglia promote interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF)-α, as well as other pro-inflammatory cytokines and cause harmful effects [17]. A direct injection of lipopolysaccharide into the CNS can drive the synthesis of IL-1β, enhance the activation of microglia, and reduce the production of Aβ levels and plaque burden [18].

CYTOKINES

Members of the interleukin family are the main components of cytokines and are named with Arabic numerals in the order of discovery. IL-1, IL-6, and TNF-α are the main inflammatory cytokines involved in Aβ deposition [19]. In the brains of patients with AD, microglia are exposed to the environment in which Aβ is deposited. This continuous stimulation causes a massive release of cytokines, which damages the neurons [20]. Studies have reported high levels of IL-1β and TNF-α in microglia around Aβ plaques in brains of patients with AD [21 –23]. A study found that IL-12 and IL-23 are produced by activated microglia in an APPPS1 AD mouse model [24]. Furthermore, studies have found that IL-17A may promote the clearance of Aβ in AD patients [25]. Members of the interleukin family are the main components of cytokines. TNF, transforming growth factor, and interferons have also been found to be possible candidate biomarkers for AD. However, cytokines such as IL-1β, IL-6, and TNF-α have been researched more extensively.

IL-1

IL- 1 plays an important role in the CNS. Early studies found that the concentration of IL-1β in the periphery was not significantly different between AD patients and normal people [21]. Due to limitations in technology for detection in the past, the concentration of IL-1β could not be detected accurately [26]. A meta-analysis in 2018, which included 34 studies, concluded that the peripheral IL-1β level in AD patients was significantly increased; however, after a Bonferroni adjustment, the results were not statistically significant [27]. Dursun et al. found that serum IL-1β levels were significantly increased in people with early onset AD [28]. Most of the recent studies have found elevated serum IL-1β levels in patients with AD [29 –31]. IL-1β has also been reported to be associated with cognitive function. King et al. found that with a decline in cognitive function, the serum IL-1β levels of AD patients gradually declined as well [32]. Their study also pointed out that IL-1β was significantly increased in the mild cognitive impairment (MCI) stage of disease progression, but no differences were found in inflammatory factors for the AD stage. This also shows that inflammation plays an important role in the early stages of cognitive impairment.

IL-6

IL-6 has a wide range of biological effects, regulates a variety of cell functions, and effectively mediates inflammatory reactions. Early in vitro experiments revealed that TNF-α and IL-1β can induce the expression of IL-6 [33]. Some reports have also shown that IL-6 can inhibit the production of TNF-α and IL-1 [34]. Recently, IL-6 in peripheral blood has been found to be a potential biomarker for AD [35]. A study including 34 MCI patients, 45 AD patients, and 28 age-matched controls observed that that serum IL-6 levels were significantly elevated in the AD group [36]. Contrastingly, other studies have yielded different results. A meta-analysis concluded that the level of IL-6 in the peripheral blood of patients with AD did not change, compared to the control group with normal cognition [27]. Some reports have suggested that compared with the normal control group, the level of IL-6 in the peripheral blood of patients with AD was significantly reduced [37]. Most studies have small sample sizes and different detection techniques, which may result in conflicting results. Presently, the correlation between IL-6 levels and cognitive impairment is a central research topic. Koyama et al. assessed a total of seven studies and found that as the level of IL-6 in the peripheral blood increased, the risk of dementia significantly increased. However, no such association has been found specifically for AD [38]. A meta-analysis of 175 studies indicated that IL-6 may be a useful inflammatory marker, which is linked to the severity of cognitive impairment [39]. This meta-analysis included highly heterogeneous studies, which may have led to the differences in results.

TNF-α

TNF plays a central role in regulating inflammatory responses [40]. The findings about the concentration of serum TNF in AD patients have not been consistent. A recent study on AD patients with depression found that the concentration of TNF-α was significantly higher than that of AD patients without depression or a normal control group [41]. Many studies have revealed that the level of TNF-α in the peripheral blood of AD patients is elevated [36]. Contrastingly, several other studies have found no significant difference or a decrease in the TNF-α concentration between patients with AD and the control groups [37, 42]. In addition, the severity of dementia also results in changes in the serum levels of TNF-α. Compared with patients with severe AD and vascular dementia, the level of serum TNF-α in patients with mild to moderate AD is reportedly lower [43]. A study found that TNF-α levels in the plasma were correlated with MMSE scores. Further, worse cognitive function was associated with lower levels of TNF-α in the plasma [44].

CHEMOKINES

Chemokines are a large group of inflammatory factors. They can be divided into four subgroups according to the different cysteine residues: CXC, CC, C, and CX3C. There is evidence that proinflammatory chemokines can drive proinflammatory cells to gather in the inflamed or damaged CNS [45]. Using primary monocyte-derived macrophages and primary adult astrocytes as a model, an in vitro cell experiment showed that certain chemokines can attract microglia to the periphery of Aβ plaques [46]. Sokolova et al. observed a continuous increase in the expression of monocyte chemotactic protein-1 (MCP-1), IL-6, and IL-8 in the brain tissue of AD patients [47]. Similarly, using primary monocyte-derived macrophages and primary adult astrocytes as a model, a study confirmed that inflammatory cytokines in the brain tissue of patients with AD can be induced by microglia [48]. These include cytokines, chemokines, complement components, etc. Chemokines play a biological role mainly by recognizing and binding to their corresponding receptors. Reviews published by Guedes et al. have shown that chemokines and their receptors are important in the pathogenesis of AD [49]. High expression levels of chemokine receptors on activated microglia have been observed in the brains of patients with AD [50]. These immunohistochemical results suggest that the expression of chemokines and receptors may be related to amyloid protein, which plays an important role in the pathogenesis of AD. Chemokines and their receptors are considered new therapeutic targets for AD [51]. The possibility of chemokines in peripheral blood being a novel biomarker of AD is becoming prominent. Previous studies have found that some chemokines (IL-8, IP-10) in the cerebrospinal fluid and peripheral blood are related to the pathology of AD [52]. Haskins et al. found that in their 3xTg-AD mouse model of AD, some chemokines in the blood appeared before any AD-associated pathological changes [53].

MCP-1

MCP-1/CCL2 is the first member discovered in the human CC family of chemokines [54]. Increased levels of MCP-1/CCL2 in the blood may be related to poor memory performance [55, 56]. The level of MCP-1/CCL2 may reflect early pathological changes and memory functions linked to AD. For the first time, a longitudinal study of a cohort of asymptomatic elderly individuals showed that the correlation between MCP-1/CCL2 levels and cognitive function may only be linked to memory function [57]. Bettcher et al. proved for the first time that elevated plasma MCP-1/CCL2 and eosinophil chemokine-1 (CCL11) can predict worse plot memory functions in AD and MCI [55]. For the first time in this study, we demonstrated that inflammatory factors are related to memory function. Eosinophil chemokine-1 is also a member of the CC family. Previous studies have found that the concentration of eosinophil chemokine-1 in the serum of patients with AD increased [58]. A two-year follow-up study pointed out that the higher the plasma MCP-1 level, the higher the severity of the disease and the faster the cognitive decline [59]. However, previous studies found that the serum MCP-1 concentration in patients with AD and MCI increased, and it was not related to the severity of the disease [60]. In clinical trials, the concentration of MCP-1 concentrations in the plasma of patients with early AD increased significantly [61], suggesting that MCP-1 may be a new biomarker for the early diagnosis of AD. Therefore, MCP-1 is a candidate biomarker of early AD, which may be linked to memory and may further help in predicting disease progression.

IP-10

Interferon-inducible protein-10 (IP-10) is a CXC chemokine. The data on IP-10 remain controversial. In AD and MCI patients, IP-10 levels in the cerebrospinal fluid increased significantly [62], but no significant results were obtained for the blood samples [63]. However, Hasni et al. proposed that plasma IP-10, MCP-1, and Macrophage inflammatory protein-1α (MIP-1α) levels were elevated in AD. In this study, the appropriate cutoff values for IP-10 and IL-13 provided 100% sensitivity and 100% specificity for AD diagnosis [64]. It should be noted that this study was conducted on the Malaysian population and a total of 39 patients with AD and 39 healthy individuals were enrolled. The important role of IP-10 and IL-13 in the diagnosis of AD needs to be verified with further studies.

IL-8

IL-8 is a CXC subfamily chemokine secreted by macrophages that can attract and activate neutrophils. Its biological effects may be neurotrophic or neurotoxic. Under normal circumstances, IL-8 can maintain the physiological functions of brain tissue; however, when the brain is inflammatory, an increase in IL-8 secretion enhances the inflammatory response of the body and causes tissue damage. The role of IL-8 in AD pathogenesis remains controversial. Studies have observed an increase in IL-8 expression in AD brain tissue. In a prospective cohort study, high levels of IL-8, IL-10, and TNF-α were observed in the plasma to predict the degree of cognitive impairment [65]. At the same time, clinical studies have revealed that the level of IL-8 in peripheral blood of patients with AD is significantly higher than that in the control group [66]. However, a clinical study in 2008 did not find a difference in IL-8 levels between the AD and control groups [67].

OTHER CHEMOKINES

MIP-1α is another member of the CC family of chemokines. One study found an increase in the level of MIP-1α in the peripheral blood of patients with AD [64]. Stromal cell-derived factor-1 (SDF-1) has garnered attention as a neuroprotective chemokine. SDF-1α/CXCR4 can promote the release of glutamate from astrocytes, regulate neuronal and synaptic transmission, and reduce Aβ deposition by activating microglia. The level of plasma SDF-1 in early AD patients is low, and the level of tau protein in the cerebrospinal fluid is negatively correlated with plasma SDF-1 concentration [68, 69]. This is consistent with its neuroprotective effects. Regulated on activation of normal T-cell expressed and secreted (RANTES) is also considered to have neuroprotective effects on AD. Cell line-based experiments have shown that treatment with RANTES can increase the survival rate of neurons [70]. A study detected the mRNA expression patterns of promising biomarkers in peripheral blood and found that the level of RANTES in the serum of AD patients decreased [71]. A study first assessed the association between glycogen synthase kinase-3b and fractalkine in AD [72]. Fractalkine is the only member of the CX3C chemokine family. This study showed that fractalkine levels in the brains of patients with early AD were significantly increased. To some extent, the results of another study support this conclusion. Compared with patients with severe AD, patients with mild to moderate AD have higher plasma fractalkine concentrations [73].

OTHER INFLAMMATORY BIOMARKERS

Complement

The complement system is a multi-molecule protein response system which can be effectively, quickly, and accurately regulated. It is divided into three core categories: intrinsic components of complement, complement regulatory components, and complement receptors. Complement can be activated through relatively independent but partially overlapping pathways, namely the classical, alternative, and lectin pathways. Studies have been carried out to assess the reliability of the complement system as a biomarker for AD. C3 is the central component of the activation process of the entire complement system. This is the intersection of the classical activation pathway and the alternative activation pathway. C3 has the highest serum content and is the most frequently detected complement component in clinical practice. A longitudinal cohort study was followed up for nearly 13 years, with the development of AD as the endpoint. Results showed that the lower the level of plasma C3, the higher the risk of AD [74]. At the same time, the study also pointed out that the level of complement C3 in AD patients had increased. A review of the extant literature revealed that serum complement C3 can also discriminate between MCI stage and cognitively normal people, which was confirmed in prospective studies [75]. C4 is the second activated component of the classical complement activation pathway. A clinical trial showed that plasma C4a levels in the AD group were significantly increased [76]. Factor H (FH) is a complement regulatory protein which plays a decisive role in the C3b fragment. The data on FH remain inconsistent, however, some studies in the past have found that the concentration of FH in the peripheral blood is increased in AD [77, 78]. Interestingly, other clinical studies have found that the plasma levels of FH are decreased in AD and MCI [79]. Hye et al. proposed that although it was observed that the plasma level of CF is elevated in AD and is related to the severity of the disease, its role as a candidate biomarker for AD remains limited [77].

C-REACTIVE PROTEIN

C-Reactive protein (CRP) is an acute-phase inflammatory protein and an increase in its level is related to a multitude of diseases. CRP can promote the production of Aβ₄₂ and can activate the complement system in the AD brain. CRP plays an important role in the pathogenesis of AD. There remains a certain degree of controversy about the serum CRP levels of patients with AD. Many previous studies have found increased serum CRP concentrations in patients with AD [80, 81]. A recent meta-analysis found a reduced serum CRP concentration in individuals with mild to moderate AD [82]. The authors speculated that CRP levels changed as the disease progressed. O’Bryant et al. pointed out that compared with the normal population, the serum level of CRP decreased during the AD stage [83]. In addition, Nilsson et al. compared other types of mental illness and found that the serum level of CRP in AD patients was significantly lower than that in other mental illnesses [84]. The higher the serum CRP level in patients with AD, the lower the MMSE score and the shorter the survival period. The results of this research are also different for different races. One study pointed out that in Mexican Americans, CRP levels are not associated with AD cognitive ability; however, there is a significant association in non-Hispanic people [85]. Previous studies have shown that CRP level is a risk factor for AD. This evidence indicates that with a diagnosis of AD, CRP levels may decrease. In addition, CRP levels continue to change over the course of the development of the disease. At the same time, certain studies have yielded negative results. A longitudinal study conducted a three-year follow-up of 1,284 elderly people and found that CRP levels were not associated with cognitive decline [86]. Although the current research remains controversial, CRP is still a promising biomarker, and its dynamic detection is of great importance. In addition, other inflammatory factors have been found to be promising biomarkers. These include α2-macroglobulin, immunoglobulin, and other inflammatory factors.

BLOOD CELL

Peripheral blood cells may be involved in AD pathogenesis and could be potentially important for disease management. Peripheral immune cells are involved in AD progression. Studies have shown that peripheral blood lymphocytes in patients with AD have undergone changes, including type, concentration, etc. [87 –89]. Chen et al. showed that AD patients have lower levels of LYM, consistent with a previous study [87]. Growing evidence indicates that in AD patients, pathological alterations take place not only in the brain tissue, but also in the blood cells, such as lymphocytes [90]. Evidently, blood lymphocytes from AD subjects can be easily available as biomarkers for preclinical and definitive diagnosis and probably drug screening.

Inflammatory markers have been found to be related with cognitive function. Some clinical trials have mentioned that with the decline in cognitive function, the levels of some inflammatory markers in the blood may decrease, including IL-8, TNF-α [65]. At the same time, the levels of inflammatory factors such as MCP-1 may increase as cognitive function worsens [55 –57]. The relationship between CRP and cognitive function is complex, and CRP may play different roles at different stages of the disease [81]. Chronic inflammation may result in the disease; however, as the disease progresses, the inflammatory response may play a beneficial role. The response yields controversial results in terms of changes in the concentration of inflammatory markers. The relationship between inflammatory markers and cognitive function still warrants further assessment. Increasing the sample size to probe different stages of the disease in order will aid in exploring the relationship between inflammatory markers and cognitive function.

CONCLUSIONS

In conclusion, we can see that the data on the concentration of inflammatory factors in the peripheral blood of patients with AD remain contradictory, and results from studies remain rather heterogeneous. We have summarized the results found in the literature, including information regarding biomarkers measured in the blood of AD (Table 1). Among other reasons, this could be due to the use of different ethnicities, methods of sample collection, preservation conditions, and detection methods. In addition, the sample size of most of the studies was small, the severity of the disease was quite different, and inflammatory diseases were rather complicated, which may have contributed to the contradictory results. Currently, the advent of new detection techniques, such as proteomics, has played a role in promoting multi-factor detection. However previously, the sensitivity and accuracy of detection techniques were low. Accordingly, the concentration of some factors could not be accurately detected. The difference in concentration between the control group and the experimental group could be observed only in large samples. Some past studies have applied the traditional ELISA detection technology, and most samples tested had IL-1 levels below the detection limit of ELISA (10 pg/ml) [26]. A recent review published in 2022 compares the application of several new detection techniques in AD blood biomarkers, highly sensitive ultrasensitive technology allows the determination of blood-based biomarkers with high sensitivity, such as NFL, which is a promising approach for ensuring an early and minimally invasive AD diagnosis [91]. With the advances in technology and the continuous improvement of sensitivity of detection, an increasing number of clinical trials have achieved meaningful results, highlighting inflammatory factors as potential candidate markers. The accuracy and sensitivity of detection techniques play a key role in the discovery of new inflammatory biomarkers. Most previous studies were cross-sectional studies with small samples; hence, a larger longitudinal cohort study is warranted. Although most of the results are inconsistent, peripheral blood inflammatory markers remain promising candidates for AD. In future clinical trials, more stringent admission criteria and grouping are warranted to obtain more valuable results.

Table 1

Summary of concentrations of Inflammatory biomarkers in the blood of AD patients

Biomarkers	Blood levels
CYTOKINES
IL-1	No significant difference [26 –28]
	Increased [29 –31]
IL-6	No significant difference [27]
	Increased [36]
	Decreased [37]
TNF-α	No significant difference [37, 43]
	Increased [37, 42]
CHEMOKINES
MCP-1	Increased [55 , 61]
IP-10	No significant difference [63]
	Increased [64]
IL-8	No significant difference [67]
Increased [65, 66]
MIP-1α	Increased [64]
SDF-1	Decreased [68, 69]
RANTES	Decreased [71]
Fractalkine	Increased [72, 73]
COMPLEMENT
C3	Increased [74]
C4a	Increased [76]
FH	Increased [77, 78]
	Decreased [79]
CRP	Increased [80, 81]
	Decreased [82 –84]

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/21-5422r2).

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