The Correlation of Tau Levels with Blood Monocyte Count in Patients with Alzheimer’s Disease

Abstract

Background:

Recent studies have shown that monocytes can phagocytize the tau protein, which may ameliorate tau-type pathology in Alzheimer’s disease (AD). However, there are few clinical studies on the relationship between monocytes and tau-type pathology in AD patients.

Objective:

We aimed to explore changes in peripheral monocytes and their association with tau protein in AD patients.

Methods:

A total of 127 clinically diagnosed AD patients and 100 age- and sex-matched cognitively normal controls were recruited for analysis of the correlation of plasma tau levels with the blood monocyte count. Cerebrospinal fluid (CSF) samples from 46 AD patients and 88 controls were further collected to analyze the correlation of CSF tau and amyloid-β (Aβ) levels with the blood monocyte count. 105 clinically diagnosed mild cognitive impairment (MCI) patients and 149 age- and sex-matched cognitively normal controls were recruited from another cohort for verification.

Results:

Compared to normal controls, AD patients showed a significant reduction in the blood monocyte count. In addition, the monocyte count of AD patients was negatively correlated with CSF t-tau and p-tau levels but not with plasma tau levels. In normal people, monocyte count lack correlation with tau levels both in plasma and CSF. Monocyte count were not correlated with CSF Aβ levels in either group but were negatively correlated with CSF tau/Aβ₄₂ levels in the AD group. We had further verified the correlations of monocyte count with CSF tau levels in another cohort.

Conclusion:

This study suggests that monocytes may play an important role in the clearance of tau protein in the brain.

Keywords

Alzheimer’s disease monocytes pathogenesis tau

INTRODUCTION

Alzheimer’s disease (AD) is the most common neurodegenerative disease among elderly individuals and is characterized by progressive cognitive decline [1]. Neurofibrillary tangles, composed of phosphorylated tau protein, are one of the most important neuropathological hallmarks of AD and aggravate neuroinflammation and neurodegeneration [2]. Thus, overproduction and insufficient clearance of tau protein may play a crucial role in the pathogenesis of AD [3].

Phagocytosis by the mononuclear phagocytic system is the most important means of cerebral amyloid-β (Aβ) and tau protein clearance, which ameliorates the pathogenesis of AD [4, 5]. As the most important component of the peripheral mononuclear phagocytic system, monocytes were found to be involved in the elimination of tau protein [6]. Recent studies found that monocytes can phagocytize the tau protein in the brain [5, 7]. Furthermore, monocytes have the ability to infiltrate the brain, compensate endogenous microglial cells and reduce inflammation-mediated nerve injury in neurodegenerative diseases [8]. Therefore, enhancing the phagocytic ability of monocytes may be a potential strategy for AD treatment. However, there is little clinical evidence supporting the tau protein scavenging effects of monocytes. In this study, we aimed to explore the changes in peripheral monocytes and their association with tau protein in AD patients.

METHODS

Study population

We recruited 127 AD patients from Chongqing Daping Hospital from January 2019 to December 2020. At the same time, 100 age- and sex-matched controls with normal cognition were recruited from the same hospital. We also recruited 105 patients with mild cognitive impairment (MCI) and 149 cognitive normal subjects from Qingdao Municipal Hospital as validation groups. Subjects were excluded for the following reasons: 1) a family history of dementia; 2) a concomitant neurological disorder that could potentially affect cognitive function or other types of dementia; 3) severe cardiac, pulmonary, or other systemic diseases or any type of tumor; 4) enduring mental illness (e.g., schizophrenia); 5) hematologic diseases or other diseases that could affect monocytes; and 6) recent acute or chronic inflammation. The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Guidelines for Good Clinical Practice. It was approved by the Institutional Review Board of Chongqing Daping Hospital (approval No.2018-140) and Qingdao Municipal Hospital (approval No. 2017-26) without reservation.

Patients’ diagnosis and sampling

The clinical diagnosis of AD was based on the criteria of the National Institute of Neurological and Communicative Diseases and Stroke/AD and Related Disorders Association and followed the protocols that we used before [9]. The MCI patients were diagnosed according to Petersen’s criteria in 1999 [10]. We collected demographic data and medical history data (such as hypertension and diabetes). In addition, the Mini-Mental State Examination (MMSE) was carried out to assess cognitive function.

Fasting venous blood was collected in EDTA tubes between 06 : 00 and 07 : 00 to avoid potential effects of the circadian rhythm. Then, we obtained plasma by centrifugation of blood samples within 1 h of collection and stored it at –80°C until use. Cerebrospinal fluid (CSF) was collected by lumbar puncture from some participants (46 AD patients and 88 controls). CSF was also stored at -80°C after centrifugation at 2,000×g at 4°C for 10 min. Informed consent from the participants was required before the collection of each specimen.

Measurements of monocytes and tau levels

The number of blood monocytes was measured by an automatic blood analyzer in the Clinical Laboratory of these two hospitals. The plasma total tau (T-tau) levels were measured using the commercially available single-molecule array (SIMOA) Human Neurology 3-Plex A assay kit (Quanterix, Lexington, MA) on the automated SIMOA HD-1 analyzer (Quanterix, Lexington, MA). Human tau and Aβ enzyme-linked immunosorbent assay (ELISA) kits (Invitrogen) were used to measure the CSF levels of T-tau, phosphorylated tau-181 (P-tau), Aβ₄₀, and Aβ₄₂. All measurement processes were performed in accordance with the manufacturer’s instructions.

Statistical analysis

This study used SPSS version 25.0 for statistical analysis. All data are expressed as the mean± standard deviation (SD). We checked all data for outliers. Then, the normality of the data was evaluated by the Kolmogorov–Smirnov test. A two-tailed independent t-test, the Mann-Whitney U test, or the chi-square test was used as appropriate to evaluate the demographic characteristics, monocyte counts and tau levels between the two groups. Spearman correlation analysis was used to assess the correlations between the blood monocyte count and tau and Aβ levels. All hypothesis testing in this paper was two sided, and p < 0.05 was regarded as statistically significant.

RESULTS

Characteristics of the study subjects

As shown in Table 1, the study consisted of 127 clinically diagnosed AD patients and 100 age- and sex-matched cognitively normal controls. AD patients and controls had no significant differences in educational years (p = 0.919). In addition, there was no correlational difference in the comorbidities of hypertension, diabetes, hyperlipidemia, coronary heart disease, and stroke history between these two groups. As expected, AD patients had lower MMSE scores than controls (11.50±4.56 versus 27.29±2.09, p < 0.001). In addition, AD patients had significant reductions in the levels of blood monocyte count (0.40±0.14×10^∧9/L versus 0.50±0. 20×10^∧9/L, p < 0.001) (Fig. 1).

Table 1

Characteristics of the study subjects

Characteristics	Control (n = 100)	AD (n = 127)	p
Age, mean (SD), y	68.05 (8.73)	67.36 (10.20)	0.573
Female, n (%)	56 (56.00)	70 (55.19)	0.894
Education level, mean (SD), y	9.26 (4.51)	9.28 (4.22)	0.919
MMSE score, mean (SD)	27.29 (2.09)	11.50 (4.56)	< 0.001
Hypertension, (%)	34 (34.00)	35 (27.56)	0.295
Diabetes, (%)	19 (19.00)	18 (14.17)	0.328
Dyslipidemia, (%)	23 (23.00)	25 (19.69)	0.544
Coronary artery disease, (%)	9 (9.00)	12 (9.45)	0.908
Stroke history, (%)	8 (8.00)	10 (7.87)	0.972

MMSE, Mini-Mental State Examination; a two-tailed independent t-test was used for age, education level and MMSE score after the Kolmogorov–Smirnov test. Percentage data used the chi-square test.

Fig. 1

Comparison of monocyte count. AD patients had significant reductions in blood monocyte levels compared with controls. The data are expressed as the mean±SD. The Mann-Whitney U test was used after testing for normality with the Kolmogorov-Smirnov test. ^***p < 0.001.

Correlation of monocyte count with plasma T-tau levels

There were no significant differences in plasma T-tau levels between AD patients and normal controls (3.97±2.26 pg/mL versus 4.16±2.10 pg/mL, p = 0.205) (Supplementary Figure 1). As shown in Fig. 2, we found that monocyte count had no correlation with plasma T-tau levels in all subjects (γ= 0.090, p = 0.176), AD (γ= –0.011, p = 0.903), and control (γ= 0.176, p = 0.079) group (Fig. 2).

Fig. 2

Correlations of monocyte count with plasma T-tau levels. Monocyte count was not correlated with plasma T-tau levels in all subjects, AD patients or controls. Spearman correlation analysis was used.

Correlation of monocyte count with CSF tau levels

We further analyzed the relationship between monocyte count and T-tau and P-tau in CSF in the brain. Of all the participants, 35 AD patients and 76 controls consented to the collection of CSF samples. As shown in Supplementary Table 1, there were no significant differences in the demographic statistics or comorbidities between the two groups that provide CSF samples. Compared with those of controls, the levels of CSF T-tau (434.8±221.7 pg/mL versus 183.3±60.08 pg/mL, p < 0.001) and CSF P-tau (71.68±36.89 pg/mL versus 41.88±15.51 pg/mL, p < 0.001) were significantly increased in AD patients (Supplementary Figure 2A, B). In addition, monocyte levels in all subjects (γ= –0.287, p = 0.001) and AD (γ= –0.349, p = 0.019) group were significantly negatively correlated with CSF T-tau levels but not in the controls (γ= –0.131, p = 0.225) (Fig. 3A). There was also no correlation between monocyte count and CSF P-tau levels in the control population (γ= –0.097, p = 0.373), while a negative correlation was found in all subjects (γ= –0.321, p < 0.001) and AD group (γ= –0.500, p = 0.001) (Fig. 3B).

Fig. 3

Correlations of monocyte count with CSF tau levels. A) Monocyte levels were significantly negatively correlated with CSF T-tau levels in all subjects and AD group but not in the control group. B) Monocyte count was significantly negatively correlated with CSF P-tau levels in all subjects and AD group but not in the control group. Spearman correlation analysis was used.

Correlation of monocyte count with CSF Aβ levels

To reveal the impact of Aβ burden on our findings, we then detected the correlation between CSF Aβ levels and monocyte count. The levels of CSF Aβ₄₀ (12541±4066 pg/mL versus 9308±4412 pg/mL, p < 0.001) and CSF Aβ₄₂ (1578±717.2 pg/mL versus 642.8±320.6 pg/mL, p < 0.001) in AD patients were significantly decreased compared with those in controls (Supplementary Fig. 2C, D). However, as shown in Fig. 4A and 4B, monocyte count had no correlation with CSF Aβ levels in either the AD (Aβ₄₂: γ= 0.170, p = 0.275; Aβ₄₀: γ= –0.167, p = 0.277) or control (Aβ₄₂: γ= 0.157, p = 0.156; Aβ₄₀: γ= 0.047, p = 0.673) group. As to all subjects, there is no correlation with CSF Aβ₄₀ levels (γ= 0.059, p = 0.510), while a negative correlation was found in CSF Aβ₄₂ levels (γ= 0.237, p = 0.008).

Fig. 4

Correlations of monocyte count with Aβ levels. A) Monocyte count was not correlated with CSF Aβ₄₂ levels in all subjects, AD or control group. B) Monocyte count was not correlated with CSF Aβ₄₀ levels in all subjects, AD or control group. C) Monocyte count was significantly negatively correlated with CSF T-tau/Aβ₄₂ levels in all subjects and AD group but not in the control group. D) Monocyte count in all subjects and AD group was significantly negatively correlated with CSF P-tau/Aβ₄₂ levels, but those in the control group were not. Spearman correlation analysis was used.

A wave of recent studies indicated that the ratio of tau and Aβ₄₂ can more effectively reflect Aβ deposition in the brain than a single marker [11, 12]. Thus, we further calculated the relationship of the CSF tau/Aβ₄₂ ratio with the monocyte count. We found that the monocyte count was negatively correlated with the CSF T-tau/Aβ₄₂ ratio and CSF P-tau/Aβ₄₂ ratio in AD patients (T-tau/Aβ₄₂: γ= –0.347, p = 0.025; P-tau/Aβ₄₂: γ= –0.326, p = 0.035) and all subjects (T-tau/Aβ₄₂: γ= –0.269, p = 0.002; P-tau/Aβ₄₂: γ= –0.235, p = 0.009). Moreover, there was no correlation between the two ratios and monocyte count in the controls (T-tau/Aβ₄₂: γ= –0.200, p = 0.069; P-tau/Aβ₄₂ γ= –0.177, p = 0.112) (Fig. 4C, D).

Verification of the correlation of monocyte count with CSF tau levels in MCI

In order to confirm our results, we collected a batch of data of MCI and normal controls. Characteristics of the verification subjects were shown in Supplementary Table 2. There were no significant differences in the demographic statistics or comorbidities between the two groups. The MMSE scores in MCI patients were lower than those in controls (21.63±2.92 versus 27.40±1.62, p < 0.001). Additionally, there is no significant difference in the monocyte count (0.50±0.16×10^∧9/L versus 0.49±0. 17×10^∧9/L, p = 0.408), CSF T-tau levels (178.8±56.12 pg/mL versus 177.4±64.16 pg/mL, p = 0.444), and CSF P-tau levels (42.40±11.18 pg/mL versus 42.08±11.91 pg/mL, p = 0.826) between MCI and normal controls (Supplementary Figure 3). The CSF T-tau levels had a significant negative correlation with monocyte count in MCI patients (γ= –0.200, p = 0.041). While there was no correlation in all subjects (γ= –0.079, p = 0.208) and control group (γ= 0.023, p = 0.781) (Fig. 5A), there was a negative tendency correlation of monocyte count with CSF P-tau levels in all subjects (γ= –0.120, p = 0.057) and MCI group (γ= –0.190, p = 0.052) (Fig. 5B). Monocytes in controls had no correlation with CSF P-tau levels (γ= –0.064, p = 0.438). These results further indicated that CSF tau levels might be decreased with the higher peripheral monocyte count.

Fig. 5

Correlations of monocyte count with CSF tau levels in verification subjects. A) Monocyte count was significantly negatively correlated with CSF T-tau levels in the MCI validation group, but not in all and control groups. B) Although monocyte count was not correlated with CSF P-tau levels in all groups, there was a negative tendency correlation in MCI patients. Spearman correlation analysis was used.

DISCUSSION

In this study, we first reported that the blood monocyte count was markedly decreased in AD patients compared with normal controls. Previous research has shown that monocyte phagocytosis is important in the elimination of peripheral tau protein and can alleviate tau-associated pathological damage [13]. Therefore, weakness in peripheral monocyte phagocytosis may accelerate the pathogenesis of neurological diseases such as AD [6].

Additionally, peripheral monocytes can invade the brain and supplement microglial cells, which contributes to the removal of central pathological substances in AD patients [8, 14]. Moreover, the activated microglia induced by Aβ trigger the migration of monocytes to the brain [15]. Hence, this unidirectional migration of monocytes would likely lead to a decline in the peripheral monocyte count in AD patients. In addition, the monocytes of AD patients show weaker phagocytic ability and are more likely to undergo apoptosis [16]. Our study found a downward trend of peripheral monocytes in AD patients, which further verifies the dysfunction in phagocytosis in AD monocytes.

In addition, we observed that CSF tau levels in AD patients were negatively correlated with the monocyte count. In another cohort consisted of MCI patients and cognitively normal subjects, similar results were found though the correlations were not as significant as the AD group. Tau protein is widely acknowledged to be present in higher levels and has increased phosphorylation in AD patients, which leads to the main pathologic impairment of AD independent of Aβ oligomers [17, 18]. A previous study confirmed that peripheral monocytes can clear the tau protein from blood and indirectly alleviate central tau phosphorylation and neuropathological damage [19]. In addition, monocytes express higher CCR2 levels, which promote the recruitment of monocytes from the blood into the brain in AD [20]. Compared with endogenous microglia, peripheral monocyte-derived cells have a greater ability to eliminate tau, resulting in a conspicuous decrease in central tau protein [21]. Therefore, the correlation between CSF tau levels and the blood monocyte count is negative, and a higher monocyte count means stronger scavenging activity. This result provides clinical evidence that monocytes can participate in the clearance of tau protein in the brain, whether directly or indirectly. While normal controls had few monocytes recruited to the brain, the correlation between the monocyte count and CSF tau levels was poor in normal controls.

Nevertheless, we found that the level of tau protein in plasma was not significantly correlated with the monocyte count. Several possible reasons should be considered as follows. First, chronic inflammation by monocytosis can cause an excess of inflammatory mediators and lead to an increase in GSK-3β levels, which would exacerbate tau expression and phosphorylation in blood [22]. Another explanation could be that plasma tau levels are more readily influenced by other peripheral tissues and remain in a dynamic balance [23]. Consequently, the relevance of monocytes to plasma tau levels was negative in our study.

Previous studies have also shown that monocytes could participate in the clearance of Aβ [4]. In addition, peripheral-derived monocytes have a stronger ability to phagocytose Aβ than microglia [24]. The increase in monocytes in the brain can greatly reduce the central Aβ burden, which alleviates downstream AD pathologies, such as phosphorylated tau and neurofibrillary tangles formation [25]. Our study also found that the monocyte count was negatively correlated with CSF T-tau/Aβ₄₂ levels and CSF P-tau/Aβ₄₂ levels in the AD group, although the correlation with CSF Aβ levels was poor. Monocytes may indirectly decrease tau protein levels in the brain by reducing Aβ plaques. This further shows that monocytes play an important role in the pathological process of AD.

In addition to the phagocytosis pathway, monocytes can partially reverse the dysfunction of microglia and improve tau pathology by compensating microglia [26]. Notably, this study is only a cross-sectional study, and further clinical follow-up should be carried out to clarify the relationship between the functions and subsets of monocytes and AD progression in the future. We also need CSF samples and PET-CT images of tau deposition from a larger sample of participants to further confirm our results. In addition, the relationship between the reduction in AD risk and increased monocyte count in chronic inflammation requires more investigation.

In conclusion, our study found that monocyte counts were significantly reduced in AD patients and negatively correlated with tau levels in CSF. This study further supports the role of monocytes in central tau clearance, and strengthening the phagocytosis function of monocytes may be a promising strategy for AD prevention and treatment.

Footnotes

ACKNOWLEDGMENTS

This study was supported by the National Natural Science Foundation of China (grant no. 81801084).

Authors’ disclsoures available online ().

The supplementary material is available in the electronic version of this article: .

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