Associations Between Plasma Klotho with Renal Function and Cerebrospinal Fluid Amyloid-β Levels in Alzheimer’s Disease: The Chongqing Ageing & Dementia Study

Abstract

Background:

The kidney-brain crosstalk has been involved in Alzheimer’s disease (AD) with the mechanism remaining unclear. The anti-aging factor Klotho was reported to attenuate both kidney injury and AD pathologies.

Objective:

To investigate whether plasma Klotho participated in kidney-brain crosstalk in AD.

Methods:

We enrolled 33 PiB-PET-positive AD patients and 33 amyloid-β (Aβ)-negative age- and sex-matched cognitively normal (CN) controls from the Chongqing Ageing & Dementia Study (CADS). The levels of plasma Klotho, Aβ, and tau in the cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay.

Results:

We found higher plasma Klotho and lower estimated glomerular filtration rate (eGFR) levels in AD patients compared with CN. The eGFR was positively associated with Aβ₄₂, Aβ₄₀ levels in CSF and negatively associated with CSF T-tau levels. Plasma Klotho levels were both negatively correlated with CSF Aβ₄₂ and eGFR. Mediation analysis showed that plasma Klotho mediated 24.96% of the association between eGFR and CSF Aβ₄₂.

Conclusion:

Renal function impacts brain Aβ metabolism via the kidney-brain crosstalk, in which the plasma Klotho may be involved as a mediator. Targeting Klotho to regulate the kidney-brain crosstalk provides potential therapeutic approaches for AD.

Keywords

Alzheimer’s disease amyloid-β estimated glomerular filtration rate kidney-brain crosstalk Klotho

INTRODUCTION

Alzheimer’s disease (AD) is the most common type of dementia for which aging is the major risk factor. An imbalance of overproduction and impaired clearance of amyloid-β (Aβ) is a very early (often initiating) event of AD [1]. Emerging evidence has indicated that the brain and the peripheral tissues and organs synergistically contribute to brain Aβ metabolism and AD pathogenesis [2]. Elucidating the crosstalk between the brain and the periphery is essential to better understanding AD.

Increasing evidence has shown that chronic kidney disease (CKD) or renal dysfunction is associated with impaired Aβ metabolism in the blood and the brain and increased risk of AD in humans [3 –5]. The kidney has the physiological function of clearing circulating Aβ, which contributes to brain Aβ clearance [3]. Our previous study found that unilateral nephrectomy could result in a 20% increase in Aβ burden in the brain and remarkable cognitive impairment in an AD mouse model [3]. These findings suggest that the kidney-brain crosstalk play important roles in AD pathogenesis. However, the mechanisms of the kidney-brain crosstalk are not fully understood.

Klotho, an well-known anti-aging protein, is highly expressed in distal convoluted tubules of the kidneys and choroid plexus of the brain [6]. Previous study has revealed that plasma Klotho is mainly secreted by the kidney [7]. Lower plasma Klotho levels were commonly found in CKD patients and animal models, which may be caused by damage of functional nephrons and inhibition of Klotho expression [8]. Recent human studies found that KL-VS heterozygosity, causing increased plasma Klotho [9, 10], is associated with lower Aβ or tau accumulation in the brain and decreased AD risk [11, 12]. These findings suggest that Klotho may participate in AD pathogenesis. Whether plasma Klotho participates in kidney-brain crosstalk in AD remains unknown.

In this study, we investigated the changes of plasma Klotho levels in AD patients, and its association with AD core biomarkers in the cerebrospinal fluid (CSF) and estimated glomerular filtration rate (eGFR). Then, we assessed the mediation roles of plasma Klotho in relationship between eGFR, an indicator of renal function, and CSF Aβ levels. We aim to provide a further understanding on the mechanisms of the kidney-brain crosstalk in AD.

MATERIALS AND METHODS

Study population

The study population was from the Chongqing Ageing & Dementia Study (CADS), which is an ongoing cohort study initiated in 2010 to explore strategies for early diagnosis and intervention on AD. Detailed procedure of the recruitment has been published elsewhere [13].

In the present cross-sectional study, AD patients with positive Aβ and age- and sex-matched cognitively normal (CN) controls with negative Aβ by PiB-PET or CSF Aβ were enrolled (January 2018 to October 2021). Subjects were excluded if they had: 1) age≤50 years; 2) a concomitant neurologic disorder that could potentially affect the cognitive function or other types of dementia; 3) severe cardiac, hepatic, or renal dysfunction; 4) disease that may affect plasma Klotho levels (e.g., hypoparathyroidism, acute inflammatory disease, etc.); 5) psychiatric disorders (e.g., schizophrenia, etc.). Finally, 33 Aβ-positive AD patients and 33 Aβ-negative CN met the criteria were enrolled in the analysis.

This study was approved by the Medical Ethics Committee of Daping Hospital, Third Military Medical University, Chongqing, China (approval number: 2021–266). Informed consent was obtained from the patients or their relatives.

AD diagnosis

The diagnosis of AD was according to the criteria of the National Institute of Aging-Alzheimer’s Association (NIA-AA) [14]. The cognitive status was assessed based on Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR)-global by experienced neurologists. AD dementia was defined by MMSE score < 24 or CDR-global≥1. Aβ status in the brain was defined by PiB-PET or CSF ATN biomarkers.

Data collection

The demographic data and medical history (including age, gender, hypertension, diabetes, coronary artery disease, liver and kidney function, current smoking, and alcohol consumption status) were collected, which were self-reported or based on outpatient/inpatient medical system.

APOE genotyping

APOE ɛ4 carriers were defined as subjects with 1 or 2 copies of allele ɛ4. DNA was extracted from whole blood using genomic DNA purification kits (Promega Biotech, Beijing) and genotyped with the human APOE gene ɛ2/ɛ3/ɛ4 genotyping kits (real time-PCR based) (Memorigen Biotech, Xiamen). All those procedures were performed according to the manufacturer’s instructions.

Amyloid PET imaging and processing

Aβ PET imaging was conducted using the Pittsburgh Compound B (PiB) according to standardized research protocols [15]. Briefly, a 20-min acquisition was started 40 min after PiB injection. Standardized uptake value (SUV) data for key regions of interest were summed and normalized to the cerebellar cortex SUV to obtain the SUV ratio (SUVR). A global measure of Aβ burden was computed using the mean SUVR in the frontal, superior parietal, lateral temporal, lateral occipital, and anterior and posterior cingulate regions. Participants were considered PiB-PET⁺ when SUVR was higher than 1.40 [16].

CSF and plasma sampling and processing

CSF and plasma were sampled and processed according to guidelines from Alzheimer’s Biomarkers Standardization Initiative (ABSI) [17] and Standardized Operating Procedures (SOPs) [18]. Briefly, CSF samples were centrifuged at 2000 g for 10 min at room temperature and then the supernatant was aliquoted and stored at –80°C until use. Fast blood samples were collected in EDTA tubes and placed at room temperature for half an hour. Then, centrifuged for at 2,000 g for 10 min at room temperature; the supernatant was aliquoted and stored at –80°C until use. Total processing time was no longer than 2 h from “stick-to-freezer”. The CSF samples of all the CN participates and 19 of AD patients enrolled were available.

Measurements of AD core biomarkers

According to global measurement standardization from the Alzheimer’s Association Global Biomarkers Consortium [19], CSF levels of Aβ₄₀, Aβ₄₂, total tau (t-tau), phosphorylated tau-181 (p-tau) were measured using enzyme-linked immunosorbent assays (ELISA) kits (INNOTEST, United States). CSF levels of neurofilament light chain (NFL) were measured using the Meso Scale Discovery-based immunoassay (K15081K, MSD). All of measurements were performed according to the manufacturer’s instructions. The cutoff values to define abnormal ATN biomarkers in CSF were Aβ₄₂ < 933 pg/mL (A+) and CSF P-tau181 > 48.7 pg/mL (T+) [20].

Measurements of plasma Klotho

Plasma Klotho levels were measured using the human Klotho-ELISA kits (Fine Biotech, Wuhan, China) according to the manufacturer’s protocol. All the participates included in this study had their plasma samples for testing.

Statistical analyses

Continuous variables were expressed as the mean ± standard deviation, and categorical variables were expressed as percentages or ratios unless special illustration. We used the Shapiro-Wilk test for normality, Student’s t test or Wilcoxon rank-sum test for continuous variables and the Chi-square test for categorical variables to compare group differences among study subjects. Spearman correlation analysis was used to examine the correlations between plasma Klotho levels with eGFR and AD core biomarkers. Partial correlation analysis was used to correct the correlation coefficient.

To determine whether and the extent to which the kidney-brain crosstalk was mediated by plasma Klotho, we conducted mediation analysis to estimate the direct effect (DE), indirect effect (IE), and total effect (TE). In our study, renal function (eGFR) was settled as exposure variable, CSF Aβ₄₂ as outcome variable, and plasma Klotho as mediating variable. The mediation analysis was conducted using the Python package (PyProcessMacro) with 5000 bootstrap resamples and 95% confidence intervals were estimated. If the confidence interval includes zero, it means that there is no significant mediating effect at the significance level of 0.05.

All hypothesis testing was two-sided, and statistical significance was defined as p < 0.05. All statistical computations were performed using GraphPad prism version 8.0, python version 3.7.4, and SPSS version 25.

RESULTS

Characteristics of study population

The demographic characteristics of the participants were summarized in Table 1. There were no significant differences in age, sex, education level or the comorbidities of hypertension, diabetes mellitus, hyperlipidemia, and chronic heart disease between AD patients and CN. Renal function remained normal in all participants. AD patients had a higher proportion of APOE ɛ4 carriers (p < 0.001) and lower MMSE scores (p < 0.001). The levels of Aβ₄₀ (p < 0.001) and Aβ₄₂ (p < 0.001) were lower, whereas t-tau (p < 0.001) and p-tau (p = 0.001) were higher in CSF of AD patients than in CN.

Table 1

Characteristics of the study participants

Characteristics	CN (n = 33)	AD (n = 33)	p
Age (y)	67.72±5.17	67.30±9.75	0.826
Sex, female (%)	18 (54.55)	20 (60.60)	0.618
Education level (y)	7.88±4.37	9.95±2.87	0.305
MMSE score	21.81±4.60	11.34±6.12	<0.001
Current smokers, No. (%)	6 (18.18)	7 (21.21)	0.757
APOE ɛ4 carriers, No. (%)	5 (15.15)	20 (64.52)	<0.001
eGFR (ml/min/1.73 m²)	149.7±31.05	116.0±22.23	<0.001
Laboratory variables (pg/ml)
CSF Aβ₄₀	16061.00±2974.94	9683.47±5823.80	<0.001
CSF Aβ₄₂	1372.50± 320.94	519.08±198.19	<0.001
CSF T-tau	127.21±31.94	656.50±608.10	<0.001
CSF P-tau₁₈₁	52.93±17.77	83.48±42.08	0.001
CSF NFL	1544.56 (778.09)	1098.06 (518.55)	0.026
Comorbidities (%)
Hypertension	10 (30.30)	10 (30.30)	>0.999
Diabetes	4 (12.12)	7(21.21)	0.322
Hyperlipidemia	2 (6.06)	7 (21.21)	0.151
CHD	3 (9.10)	5 (15.15)	0.706

Values are expressed as mean±SD, median (IQR), or percentage, appropriately. MMSE, Mini-Mental State Examination; APOE, apolipoprotein E; eGFR, estimated Glomerular filtration rate; CSF, cerebrospinal fluid; Aβ, amyloid-β; T-tau, total tau; P-tau, phosphorylated tau; NFL, neurofilament light chain; CHD, chronic heart disease.

Comparison of plasma Klotho between AD and CN

To explore whether plasma Klotho participates in AD, we investigated the changes of plasma Klotho in AD. We found that plasma Klotho concentrations were higher in AD patients compared with CN (AD: 846.42±564.103 pg/mL; CN: 575.46±394.468 pg/mL; p = 0.033) (Fig. 1A). The difference remained significant after adjusting for age and sex (p = 0.035). Besides, there was no significant difference in plasma Klotho levels between APOE ɛ4 carriers and non-carriers (Fig. 1B).

Fig. 1

Plasma Klotho levels in AD patients and CN. Comparison of the plasma Klotho levels between the CN and AD patients (A). Comparison of plasma Klotho levels between the APOE ɛ4 non-carriers and carriers (B). CN, cognitive normal controls; AD, Alzheimer’s disease; APOE, apolipoprotein E; NS, no significance.

Correlation between plasma Klotho and AD biomarkers

Next, we analyzed the correlation between plasma Klotho with AD CSF biomarkers in 19 AD patients and all CN whose CSF samples were available (Fig. 2). In the total sample,plasma Klotho concentrations were negatively correlated with CSF Aβ₄₂ levels (r = –0.341, p = 0.013), but not with CSF Aβ₄₀, t-tau, p-tau₁₈₁, or NFL levels. No significant correlation was found within the AD (r = 0.029, p = 0.874) or CN subgroups (r = –0.383, p = 0.106), probably due to the small sample sizes.

Fig. 2

Associations between plasma Klotho with AD biomarkers. Relationship between plasma Klotho and CSF Aβ₄₂ (A), Aβ₄₀ (B), t-tau (C), p-tau181 (D), and NFL (E). The best-fit regression line is shown, and 95% confidence intervals are superimposed. CSF, cerebrospinal fluid; Aβ, amyloid-β; T-tau, total-tau; P-tau, phosphorylated tau; NFL, neurofilament light chain; ns, no significance.

Correlation between eGFR with plasma Klotho and AD biomarkers

Plasma Klotho is mainly secreted by the kidney, which in turn regulates renal function [21]. Therefore, we firstly investigated the relationship between eGFR with plasma Klotho. The result showed that plasma Klotho levels were negatively associated with eGFR in total sample (r = –0.432, p = 0.001), suggesting that the decline of renal function may trigger Klotho secretion (Fig. 3A).

Fig. 3

Associations between eGFR with plasma Klotho and AD biomarkers. Association between eGFR with Klotho in plasma (A), and Aβ₄₂ (B), Aβ40 (C), T-tau (D), P-tau (E) and NFL (F) in CSF in all subjects. The best-fit regression line is shown, and 95% confidence intervals are superimposed. eGFR, estimated glomerular filtration rate; CSF, cerebrospinal fluid; Aβ, β-amyloid; T-tau, total-tau; P-tau, phosphorylated tau; NFL, neurofilament light chain; ns, no significance.

Kidney is an important organ for Aβ clearance in the periphery. Thus, we further analyzed the correlation between eGFR and AD CSF biomarkers. The result showed that eGFR had a positive correlation with CSF Aβ₄₂ levels (r = 0.419, p = 0.003) and CSF Aβ₄₀ levels (r = 0.322, p = 0.024), and a negatively correlation with CSF T-tau levels (r = –0.360, p = 0.015) (Fig. 3B-D), implying that renal function may impact brain Aβ clearance. No significant correlation was found between eGFR with CSF P-tau₁₈₁ and NFL (Fig. 3E, F).

Mediation effect of plasma Klotho on the relationship between eGFR and CSF Aβ₄₂

Next, we investigated whether plasma Klotho participated in kidney-brain crosstalk. We conducted a mediation analysis to assess the mediate effects of plasma Klotho in the association between eGFR and CSF Aβ₄₂ levels. The results confirmed that there was an association between plasma Klotho and CSF Aβ₄₂. Besides, plasma Klotho mediated the indirect effect (all confidence interval does not include zero), as a complementary partial mediation (mediated effect and direct effect both exist and point at the same direction), which was estimated to explain 24.96% of the association between eGFR and CSF Aβ₄₂. There was also a significant direct effect of eGFR on CSF Aβ₄₂ (all p < 0.05) (Fig. 4). As a support, we conducted partial correlation analysis and found that there was still a significant correlation between plasma Klotho and CSF Aβ₄₂ levels (r = –0.314, p = 0.030) after adjusting for eGFR, suggesting that Klotho may also regulate CSF Aβ₄₂ levels via other pathways.

Fig. 4

Mediation analysis for indirect effect of plasma Klotho on the relationship between eGFR and CSF Aβ₄₂. IE is expressed as effect value (Boot LLCI, Boot ULCI), DE and TE are expressed as effect value (p value). DE, direct effect; IE, indirect effect; TE, total effect; LLCI, lower level of confidence interval; ULCI, upper level of confidence interval; eGFR, estimated glomerular filtration rate; CSF, cerebrospinal fluid; Aβ, amyloid-β.

DISCUSSION

Increasing evidence has indicated that the kidneys play important roles in maintaining cognition and other physiological function of the brain, suggesting that there exists crosstalk between the kidneys and the brain [5 , 23]. Kidney also physiologically regulates Aβ metabolism [3]. Renal function decline, such as CKD or unilateral kidney removal, is associated with higher Aβ burden in the brain and higher AD risk [4, 24]. In the present study, we found that the eGFR was lower in AD patients than in CN, the lower eGFR was associated with lower Aβ₄₂ and Aβ₄₀ levels, and higher T-tau levels in CSF, which implies higher Aβ deposition and neurodegeneration in the brain. These findings suggest that the kidney-brain crosstalk may be involved in AD pathogenesis. But the underlying mechanisms of the kidney-brain crosstalk in AD remain largely unknown.

Here, we found that plasma Klotho was associated with both eGFR and CSF Aβ₄₂ levels; the mediation analysis showed that plasma Klotho mediated 24.96% of the association between eGFR and CSF Aβ₄₂. It implies that plasma Klotho may serve as a mediator of kidney-brain crosstalk to mediate the effects of renal function on the brain Aβ metabolism in further. Additionally, plasma Klotho levels were higher and eGFR was lower in AD patients compared with CN, suggesting that Klotho-regulated kidney-brain crosstalk might participate in AD pathogenesis. Moreover, Klotho serves as a rejuvenation factor in aging process for its roles of suppressing accelerated aging process [25]. Aging is a major risk factor of AD, and results in declined function of the whole body. As well, the metabolism of Aβ and the pathogenesis of AD are involved in both the brain and the peripheral tissues and organs (reviewd in [2]). Increasing evidence have shown that the decline of the systemic function during aging, such as phagocytosis of monocytes [26], BBB dysfunction [13, 27], gut dysbiosis [28], and accumulation of systemic pro-aging factors [29], etc., were associated with compromised Aβ clearance and increased AD risk. Therefore, besides regulating the kidney-brain crosstalk, plasma Klotho may also play protective roles against AD via anti-aging of the whole body.

Additionally, the partial mediation effect of plasma Klotho suggests that renal function also impact brain Aβ metabolism via other pathways. Actually, substantial crosstalk occurs between the kidney and the brain in AD via multiple pathways. Firstly, the kidneys have physiological function of clearing metabolites or toxins, thus maintaining the environmental homeostasis of the body and the brain. On the one hand, the kidneys remove creatinine, methylglyoxal [30], IL-1β [31], β2-microglobulin [32], etc., and impact cognitive function in an Aβ-independent pathway. On the other hand, as we have reported recently, the kidneys have physiological Aβ clearance function, which impact AD pathogenesis in an Aβ-dependent pathway. Secondly, the kidneys have physiological secretion function of neurotrophins [22], such as erythropoietin, uric acid, and vitamin D–calcitriol, which are reported to be protective for cognition. Taken together, the kidney-brain crosstalk participates in AD pathogenesis in Aβ-dependent and -independent manners.

Identifying the messengers and clarifying the mechanisms of the kidney-brain crosstalk in AD is key issues to be resolved in the future, such as vascular factors, the RAS system, erythropoietin, 1,25(OH) 2 D, etc. [22, 33], which is critical to maintain brain health and may provide potential therapeutic targets and approaches for AD. Circulating blood is a critical pathway of kidney-brain crosstalk [29]. Regulation in systemic factors in blood via multiple experimental models, such as parabiosis [34], hemodialysis [35], and blood exchange [36], has been demonstrated to reduce amyloid pathology within the brain and improve cognitive function in AD models; our previous study also showed that enhancing Aβ clearance function of the kidneys could contribute to clearing brain Aβ and delaying AD progression in AD mouse model. These findings suggest that the capacity of the kidney to regulate certain substances in the peripheral circulation has the potential to influence AD pathogenesis.

In our present study, plasma Klotho levels were negatively correlated with eGFR, which is different from previous studies that found a decreased plasma Klotho among CKD patients [37]. This may be because that the participants enrolled in this study had renal function within normal reference range (eGFR: 134.228±31.996 ml/min/1.73 m²), in which the increase of plasma Klotho with the decrease of eGFR may be a compensatory response [21]. Moreover, our findings should be interpreted cautiously due to the cross-sectional design and small sample size. Our results need to be verified in larger-scale populations, and the roles of kidney-derived Klotho in cerebral Aβ metabolism and its therapeutic potential for AD need to be verified in prospective and intervention studies in further.

In conclusion, our study suggests that the kidney-brain crosstalk may involve in AD pathologies, providing clues to understand AD pathogenesis from the systemic perspective. Plasma Klotho may act as a messenger participating in the kidney-brain crosstalk in AD. Targeting Klotho to regulate the kidney-brain crosstalk may offer novel opportunities for AD intervention.

Footnotes

ACKNOWLEDGMENTS

The authors thank the CADS-participants and CADS-team members for collecting the data.

FUNDING

This study was supported by National Natural Science Foundation of China (NSFC) (grant no. 82120108010 and 81930028 to Y.J.W., 82171418 to J.W.).

CONFLICT OF INTEREST

The authors declare no conflict of interest.

DATA AVAILABILITY

The data that support the findings of this study are available on request from the corresponding author.

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Associations Between Plasma Klotho with Renal Function and Cerebrospinal Fluid Amyloid-β Levels in Alzheimer’s Disease: The Chongqing Ageing & Dementia Study

Abstract

Background:

Objective:

Methods:

Results:

Conclusion:

Keywords

INTRODUCTION

MATERIALS AND METHODS

Study population

AD diagnosis

Data collection

APOE genotyping

Amyloid PET imaging and processing

CSF and plasma sampling and processing

Measurements of AD core biomarkers

Measurements of plasma Klotho

Statistical analyses

RESULTS

Characteristics of study population

Comparison of plasma Klotho between AD and CN

Correlation between plasma Klotho and AD biomarkers

Correlation between eGFR with plasma Klotho and AD biomarkers

Mediation effect of plasma Klotho on the relationship between eGFR and CSF Aβ42

DISCUSSION

Footnotes

ACKNOWLEDGMENTS

FUNDING

CONFLICT OF INTEREST

DATA AVAILABILITY

References

Mediation effect of plasma Klotho on the relationship between eGFR and CSF Aβ₄₂