Alzheimer's disease and antibody-mediated immune responses to infectious diseases agents: A mendelian randomization study

doi:10.21203/rs.3.rs-4853251/v1

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Alzheimer's disease and antibody-mediated immune responses to infectious diseases agents: A mendelian randomization study

https://doi.org/10.21203/rs.3.rs-4853251/v1

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Background

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder, with antibody-mediated immune responses to infectious diseases agents potentially playing a decisive role in its pathophysiological process. However, the causal relationship between antibodies and AD remains unclear.

Methods

A two-sample Mendelian randomization (MR) analysis was conducted to investigate the causal link between antibody-mediated immune responses to infectious diseases agents and the risk of AD. Genetic variations associated with these antibodies and data on AD were both obtained from the UK Biobank, utilizing its extensive repository of genome-wide association studies (GWAS) for a comprehensive analysis. The MR analysis employed the inverse variance-weighted, MR-Egger, and weighted median methods. Sensitivity analysis was also performed using MR-Egger regression, MR-pleiotropy residual sum, and outlier tests.

Results

Seven causal associations were identified between antibody-mediated immune responses to infectious diseases agents and AD. Anti-polyomavirus 2 IgG, Polyomavirus 2 JC VP1 antibody, anti-Merkel cell polyomavirus IgG, and anti-varicella zoster virus IgG and varicella zoster virus glycoproteins E and I antibody suggest a protective association with AD. Conversely, higher levels of Toxoplasma gondii p22 and Epstein-Barr virus EBNA-1 antibody appear to be associated with an increased risk of AD.

Conclusion

Our MR analysis has revealed a causal relationship between antibody-mediated immune responses to specific infectious disease agents and AD. These findings provide valuable insights into the pathophysiological mechanisms underlying AD.

antibodies

Alzheimer's disease

causality

GWAS

Mendelian randomization

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the leading cause of dementia among the elderly. Clinical manifestations of AD include memory impairment, difficulties in abstract thinking and computational abilities, and alterations in personality and behavior^1,2. The characteristic pathological changes in AD involve the excessive deposition of Aβ plaques, hyperphosphorylated tau protein forming neurofibrillary tangles, and neuroinflammatory responses due to overactivated microglia^3,4. In 2019, the International Alzheimer's Association estimated that over 50 million people worldwide suffer from AD, with projections indicating a doubling of cases by 2050, significantly escalating the socio-economic burden⁵. Despite being identified over a century ago, the precise pathogenesis of AD remains incompletely understood.

Traditionally, the brain was considered a sterile environment due to the presence of the blood-brain barrier. However, recent studies have revealed the presence of bacterial communities in post-mortem human brain tissues, suggesting that microorganisms may directly affect the brain⁶. There is substantial evidence linking AD with various pathogens, including human herpesviruses, Chlamydia pneumoniae, Helicobacter pylori, and several periodontal pathogens⁷. Emerging research indicates that β-amyloid protein may serve physiological roles, acting as a defense mechanism against potential AD-inducing infections by viruses, bacteria, and fungi. It functions as a natural antimicrobial peptide⁸ and can directly kill pathogens⁹. Patients infected with herpes simplex virus have a twofold increased risk of developing dementia in old age compared to controls. Active antiviral treatment in HSV-infected individuals can prevent AD onset up to 10 years later. Another study demonstrated that populations successfully eradicating Hp exhibited improved cognitive function after a 2-year follow-up¹⁰. Animal experiments also revealed increased astrocyte numbers in the brains of Hp-infected mice, indicative of neuroinflammation¹¹. Although multiple studies have established a connection between pathogen infection and AD, the specific causal relationship remains contentious. Therefore, understanding the potential causal relationship between pathogen infection and AD is crucial for the prevention and treatment of AD.

To address the inherent potential confounding factors in observational studies, MR provides an effective method. This approach introduces intermediate variables, namely instrumental variables (IVs), to analyze the causal relationship between exposure factors and outcomes. Utilizing publicly available genome-wide association studies GWAS data, our study aims to investigate the potential role of antibody-mediated immune responses to infectious agents in the pathogenesis of AD. We employed a two-sample MR analysis to assess this relationship. Additionally, we evaluated the association between genetic predisposition to AD and antibody-mediated immune responses to infectious agents, thereby gaining a clearer understanding of the interplay between AD and these immune responses.

2.1. Study design

In the current study, pooled data from the published genome-wide association studies (GWASs) of 46 antibodies and AD were utilized. Firstly, genetic variants associated with each antibody were selected to identify the causal relationship of each antibody with AD. Secondly, AD-associated genetic variants were employed to infer causality between AD and antibodies, respectively. The MR approach relied on three key assumptions: (1) Strong association of genetic variants used as instrumental variables with exposure; (2) No association of genetic variants with any confounders; (3) Absence of a direct correlation between genetic variation and the outcome, except through exposure ¹². As all data used were publicly available, no additional ethical approval was required. The specific study design is depicted in Fig. 1.

2.2. GWAS sources

The GWAS summary data of AD utilized in this Mendelian Randomization (MR) analysis were derived from the GWAS meta-analysis¹³ The study leveraged extensive data from the UK Biobank, including a GWAS on family history of AD involving 53,042 unique individuals and 355,900 controls. The exposure data source for this MR study is the UK Biobank, which recruited over half a million British adults between 2006 and 2010. Among these, a subsample of 9,724 participants provided serum samples for serological measurements of 20 different microorganisms. These samples were tested for total antibody levels against multiple antigens¹⁴.

2.3. The selection of IVs

In our Mendelian randomization analysis, we employed IVs as tools to discern the causal relationships between exposure factors and outcomes. IVs are typically genetic variants, with SNPs being the variant of choice for their commonality. To ensure an adequate number of SNPs for further MR analysis, a significance threshold of P < 5×10^− 6 was selected when screening for SNPs related to each antibody and AD. a substantial clumping window over 10,000 kb, and minimal linkage disequilibrium (r² < 0.001), as these measures ensure the SNPs' independence¹⁵. Concurrently, we scrutinized the Phenoscanner database to confirm that our selected SNPs were not associated with any known confounders. Moreover, to affirm the robustness of the association between IVs and the exposure, we utilized the F statistic as a gauge of validity¹⁶. In this study, the inclusion criteria for SNPs demanded F values exceeding 10, thus minimizing the risk of weak instrument bias. Palindromic SNPs, specifically those with A/T or G/C alleles, were systematically identified and excluded to prevent the ambiguity they can cause regarding the effect allele in GWAS studies of both exposure and outcome. To address and rectify the presence of horizontal pleiotropy, we employed the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) tool for both global and outlier analyses, rooting out SNPs exhibiting such effects¹⁷. In our study, a nominal causal effect was deemed to be the one that falls within the range of a p-value from 0.05 to the adjusted value.

2.4. Statistical analysis

To estimate the causal effect, we utilized the inverse variance weighted (IVW) method as our primary analytical approach. The IVW model is particularly potent for detecting causality within the framework of two-sample MR analysis¹⁸. We translated our findings into odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). Heterogeneity within the IVW estimates was evaluated using Cochran's Q test, where a p-value less than 0.05 signified heterogeneity. Nevertheless, heterogeneity does not inherently invalidate the IVW model. Given the diversity in causal estimates from different variants, the multiplicative random effects model was deemed preferable to the fixed effects model, and was therefore adopted for our main analysis.

Furthermore, we employed the MR-PRESSO method to identify and correct for outliers in the IVW linear regression¹⁷. The MR-Egger method, which accommodates non-zero intercepts, was applied to check for the presence of directional pleiotropy. We also conducted leave-one-out analyses to determine the influence of individual SNPs on our results. Using MR-PRESSO, we were vigilant in detecting and excluding outliers promptly. Following outlier removal, the MR analyses were revisited. All computations and statistical analyses were facilitated by the R software (version 4.3.2), utilizing the TwoSampleMR package. In cases where IVW analysis yielded a significant result (P < 0.05) and no evidence of horizontal pleiotropy or heterogeneity was found, the result could be considered positive, even if other methods did not yield a significant result, as long as the direction of the beta remained consistent.

3.1. Causal impact of antibodies on AD

The causal relationships of 46 antibodies associated with antibody-mediated immune responses to infectious disease agents on AD are depicted in Fig. 2 and detailed in Tables S12. Using the IVW method, we tested the 46 antibodies and identified 12 that showed a causal association with AD. These 12 antibodies were selected for further MR analyses. The specifics of the SNP information (SD, R2, F) for the 12 significant antibodies in the MR analyses are provided in Tables S1-11.

Through primary IVW method test for 12 antibodies, we discovered that 7 antibodies - anti-polyomavirus 2 IgG, Polyomavirus 2 JC VP1 antibody, anti-Merkel cell polyomavirus IgG, and anti-varicella zoster virus IgG and varicella zoster virus glycoproteins E and I antibody, Toxoplasma gondii p22 antibody, Epstein-Barr virus (EBV) EBNA-1 antibody - showed causal association with AD (Fig. 3). The risk of AD may be inversely linked to Anti-polyomavirus 2 IgG seropositivity (OR = 0.9275, CI: 0.9041–0.9514, P < 0.001), Polyomavirus 2 JC VP1 level(OR = 0.8685, CI: 0.8232–0.9163, P < 0.001) and Anti-Merkel cell polyomavirus IgG seropositivity(OR = 0.9673, CI: 0.9432–0.9920, P = 0.0098, Anti-varicella zoster virus IgG seropositivity (OR = 0.9711, CI: 0.9510–0.9916, P = 0.0059), Varicella zoster virus glycoproteins E and I antibody levels(OR = 0.9276, CI: 0.8883–0.9686, P < 0.001) and positively associated with Toxoplasma gondii p22 levels (OR = 1.0186, CI: 1.0023–1.0352, P = 0.0254), Epstein-Barr virus EBNA-1 antibody levels (OR = 1.1048, CI: 1.0755–1.1349, P < 0.001). In summary, anti-polyomavirus 2 IgG, Polyomavirus 2 JC VP1 antibody, anti-Merkel cell polyomavirus IgG, and anti-varicella zoster virus IgG functioned as protective factors; however, Toxoplasma gondii p22 antibody and Epstein-Barr virus EBNA-1 antibody functioned as an anti-protective factor.

3.2. Sensitivity analysis

Following the Cochrane's Q test, no heterogeneity was detected in Toxoplasma gondii p22 antibody levels, whereas heterogeneity was observed in the other six antibodies. The MR Egger regression intercept did not identify any SNP pleiotropy (Table 1). The scatter plot indicates that anti-polyomavirus 2 IgG, Polyomavirus 2 JC VP1 antibody, anti-Merkel cell polyomavirus IgG, and anti-varicella zoster virus IgG and Varicella zoster virus glycoproteins E and I antibodies may have a protective effect on AD, while Toxoplasma gondii p22 antibodies, Epstein-Barr virus EBNA-1 antibody levels may increase the risk of AD. MR analysis includes the IVW method, MR Egger method, weighted median method, and simple mode, all represented in scatter plots with specified weights. An upward sloping line indicates a positive correlation between infectious disease antibodies and AD, while a downward sloping line indicates a protective association (Fig. 4). No outliers were detected between infectious disease antibodies and AD using the retention method analysis (Fig. 5), indicating that the revealed causal relationship is not influenced by instrumental variables. Furthermore, the funnel plots of all results confirm the absence of horizontal pleiotropy (Fig. 6).

Table 1: Heterogeneity and pleiotropy analysis of mendelian randomization analysis.
Exposure	MR-Egger intercept		Cochrane's Q IVW		Cochrane's Q IVW Egger
Exposure	intercept value	P Value	Q Value	P Value		Q Value	P Value
Anti-polyomavirus 2 IgG seropositivity	-0.00012	0.98752	155.44535	<.001		155.44450	<.001
Polyomavirus 2 JC VP1 antibody levels	-0.00059	0.95579	183.00676	<.001		182.99352	<.001
Anti-Merkel cell polyomavirus IgG seropositivity	-0.00239	0.77367	155.28707	<.001		155.00510	<.001
Toxoplasma gondii p22 antibody levels	0.00081	0.89988	33.36176	0.64035		33.34571	0.59549
Anti-varicella zoster virus IgG seropositivity	-0.00770	0.32993	40.91678	<.001		39.36232	<.001
Varicella zoster virus glycoproteins E and I antibody levels	-0.00353	0.64143	148.04532	<.001		147.44643	<.001
Epstein-Barr virus EBNA-1 antibody levels(EBV-EBNA-1)	0.00100	0.83845	210.98153	<.001		210.88571	<.001

3.3. Influence of AD on 46 antibodies

We also analysed the causal effect of AD on antibodies, the insufficiency of robust IVs impeded the establishment of conclusive causal inferences.

This study employed Mendelian randomization to explore potential associations between antibody-mediated immune responses to infectious disease agent and the risk of AD. Our findings indicate that antibodies such as anti-polyomavirus 2 IgG, Polyomavirus 2 JC VP1 antibodies, anti-Merkel cell polyomavirus IgG, and anti-varicella zoster virus IgG and varicella zoster virus glycoproteins E and I antibodies are linked to a reduced risk of AD. Conversely, elevated levels of Toxoplasma gondii p22 antibodies and Epstein-Barr virus EBNA-1 antibodies are associated with an increased risk of AD. These insights highlight the intricate interplay between immune responses and neurodegenerative diseases.

4.1.1. Antibody-mediated immune responses to polyomavirus infections reduced AD Risk

Polyomaviruses are a group of non-enveloped DNA viruses, including BK, JC, Merkel cell polyomavirus, and various other types, commonly widespread in the population, but potentially causing diseases in individuals with compromised immune systems¹⁹.

It is noteworthy that previous studies have identified gene dysregulation associated with neuroinflammation, blood-brain barrier integrity, and neurodegenerative diseases in the brains of patients with progressive multifocal leukoencephalopathy infected with JC Polyomavirus. Employing Mendelian randomization, the current study has brought to light a protective correlation between anti-polyomavirus 2 IgG, Polyomavirus 2 JC VP1 antibody levels, and anti-Merkel cell polyomavirus IgG seropositivity in the context of AD. These findings underscore a paradoxical role of polyomavirus infections, where thepresence of antibodies may offer neuroprotection against AD through yet-to-be-determined pathways. These insights provide a novel perspective for future research, exploring the intricate interactions between viral infections and the pathogenic mechanisms underlying neurodegenerative diseases.

The detection of anti-polyomavirus 2 IgG seropositivity indicates previous exposure or infection, suggesting the individual has mounted an adaptive immune response, and implying the development of immune memory. This immunological imprinting may confer a degree of protection against future viral encounters and intriguingly, may extend to a potential prophylactic effect against neurodegenerative conditions like AD²⁰. The premise here is that immune memory could act to suppress viral reactivation, thereby attenuating the inflammatory cascade that is often associated with neurodegenerative pathologies.

In addition, the measurement of JC Polyomavirus VP1 antibody levels serves as a significant biomarker for assessing an individual's immune history concerning past infections. JC Polyomavirus is of particular interest due to its association with demyelinating diseases of the central nervous system, such as progressive multifocal leukoencephalopathy. The neurotropic nature of JC Polyomavirus suggests a possible link to neurodegenerative conditions, as it possesses the ability to invade the central nervous system, particularly in states of immunocompromise. Elevated antibody titers could be indicative of an increased risk for active infection or viral replication^21,22. However, the findings of this study suggest that higher antibody levels may correlate with a protective effect against AD²³, potentially indicating an effective immune clearance or control of the virus, thus minimizing its detrimental effects on the nervous system.

Moreover, the presence of anti-Merkel cell polyomavirus IgG seropositivity typically reflects an antecedent infection, which could indicate either a latent viral status or a past active infection²⁴. Merkel cell polyomavirus a human polyomavirus implicated in Merkel Cell Carcinoma, a rare and aggressive form of skin cancer, has been studied for its systemic implications beyond oncogenesis^25,26. Interestingly, this study posits an inverse relationship between Merkel cell polyomavirus seropositivity and the risk of AD. It is hypothesized that the host immune response to Merkel cell polyomavirus may modulate the immune system in ways that confer protection against the pathophysiological processes related to AD. Nevertheless, the complexity of this relationship necessitates further empirical research to elucidate the exact mechanisms involved.

It is noteworthy that previous studies have identified gene dysregulation associated with neuroinflammation, blood-brain barrier integrity, and neurodegenerative diseases in the brains of patients with progressive multifocal leukoencephalopathy infected with JC polyomavirus²⁷. Employing Mendelian randomization, the current study has brought to light a protective correlation between anti-polyomavirus 2 IgG, JC VP1 antibody levels, and anti-Merkel cell polyomavirus IgG seropositivity in the context of AD. These findings underscore a paradoxical role of polyomavirus infections, where thepresence of antibodies may offer neuroprotection against AD through yet-to-be-determined pathways. These insights provide a novel perspective for future research, exploring the intricate interactions between viral infections and the pathogenic mechanisms underlying neurodegenerative diseases.

4.1.2. Antibody-mediated immune responses to varicella zoster virus infections reduced AD Risk

This study, through Mendelian randomization, found that anti-varicella zoster virus IgG seropositivity and levels of antibodies against specific varicella zoster virus glycoproteins E and I are associated with a reduced risk of AD.The presence of anti-varicella zoster virus IgG antibodies and varicella zoster virus glycoprotein E and I antibodies typically indicates that an individual has acquired immunity to varicella zoster virus, either through previous infection or vaccination^28,29.varicella zoster virus infection, particularly shingles, has been linked to an increased risk of AD and other dementias^30–32.Although varicella zoster virus itself does not directly cause the hallmark pathologies of AD, such as β-amyloid and tau protein accumulation, it may contribute indirectly by inducing neuroinflammation and reactivating latent herpes simplex virus type 1 in the brain, which is strongly associated with AD pathogenesis^33,34. Vaccination against shingles and antiviral treatments have been shown to decrease the risk of dementia, further supporting the potential involvement of varicella zoster virus in AD development³⁵.Therefore, controlling active herpesvirus infections may be more critical for reducing AD risk than merely increasing antibody levels³⁶.This finding underscores the potential role of varicella zoster virus vaccination in mitigating the risk of AD.

4.1.3. Antibody-mediated immune responses to Toxoplasma gondii infections increased AD Risk

In this study, a Mendelian randomization approach revealed that an increase in Toxoplasma gondii p22 antibody levels is associated with an elevated risk of AD. Toxoplasma gondii is a protozoan parasite that can invade the human central nervous system, potentially leading to a range of serious health issues, particularly in individuals with compromised immune function³⁷. Congenital toxoplasmosis primarily harms the central nervous system of the fetus, which can cause miscarriages, stillbirths, brain necrosis, hydrocephalus, and mental disorders³⁸. The p22 protein, also known as SAG2 (Surface Antigen 2), is a major immunogenic antigen of Toxoplasma gondii. Measuring antibody levels against p22/SAG2 in an individual's serum can serve as a marker for T. gondii infection. Toxoplasma gondii p22 antibody levels refer to the concentration of specific antibodies against the p22 protein of T. gondii in an individual's serum. The p22 protein is one of the several antigens of T. gondii, and antibodies against it can serve as a marker for infection with this parasite^39,40.

Several studies have reported a higher prevalence of T. gondii infection in patients with AD compared to healthy controls, suggesting a possible link between the parasite and the neurodegenerative disease⁴¹. However, other studies found no significant association⁴² T. gondii infection can induce hallmarks of AD pathology in mouse models, including beta-amyloid plaques, hyperphosphorylated tau protein, neuronal death, and loss of NMDA receptors⁴³. Further large-scale studies are needed to clarify the potential role of this parasite as a risk factor or causative agent for AD.

4.1.4. Antibody-mediated immune responses to Epstein-Barr virus infections increased AD Risk

Epstein-Barr virus (EBV) is a widely spread herpesvirus that infects over 90% of adults worldwide for a long time⁴⁴. EBNA-1 antibody levels can evaluate the immune status and past infection status of the body. A cohort study report suggests that the use of antiviral drugs in herpesvirus patients is associated with a reduced risk of dementia^45,46. Currently, the specific mechanism linking EBV infection and AD is not clear, but existing research has proposed several possible mechanisms. Continuous EBV infection and repeated reactivation may promote the formation of protein plaques in the brain ⁴⁷. The study by Carbone et al. showed that the duration of the EBV incubation period may exacerbate the systemic immune response and induce changes in the inflammatory process, leading to a decrease in cognitive ability during aging⁴⁸. Our MR analysis found that Epstein-Barr virus EBNA-1 antibody levels increase the risk of AD, suggesting potential effects of immune mechanisms. Further research is needed to determine whether EBV reactivation is involved in triggering the onset or progression of AD.

4.1.5. Limitation

This study employs a Mendelian randomization approach to uncover the potential associations between antibody-mediated immune responses to infectious diseases agents and the risk of AD, yet it acknowledges several limitations.

Firstly, the results for certain antibody levels exhibit heterogeneity, including Anti-polyomavirus 2 IgG, Polyomavirus 2 JC VP1, Anti-Merkel cell polyomavirus IgG, Anti-varicella zoster virus IgG, Varicella zoster virus glycoproteins E, and Epstein-Barr virus EBNA-1, which may affect the accuracy of interpretation. Secondly, the data are primarily derived from the UK Biobank, consisting predominantly of individuals of European ancestry, thus limiting the generalizability of the findings. Additionally, the constraints related to the database and sample size, along with the inability to validate findings across multiple databases, impact the robustness of the study. While the study offers new insights into the potential causal relationships between viral infections and AD, these results do not directly establish causality. Further epidemiological research, laboratory studies, and clinical trials are necessary to validate these findings, with large-scale, multi-ethnic population studies required to confirm and extend these observations.

This study, employing Mendelian randomization, discovered that antibody-mediated immune responses to infectious diseases agents, such as anti-polyomavirus and anti-varicella zoster virus antibodies, are associated with a decreased risk of AD, while others, including antibodies against Toxoplasma gondii and Epstein-Barr virus, correlate with an increased risk. These findings highlight the complexity of immune system responses and lay the groundwork for future research to further explore the role of immune modulation in the pathogenesis of AD. Although the study provides significant insights, broader epidemiological and experimental research is necessary to validate these conclusions.

Ethical Approval

Since the data used are publicly available in the database, no additional ethical approval was needed in this case.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

Conceptualization: Jiayuan Zhang, Yao Peng, Linwen Deng.

Data curation: Mingming Wang, Dong Wang.

Formal analysis: Jiayuan Zhang.

Investigation: Jiayuan Zhang.

Methodology:Jiayuan Zhang, Linwen Deng, Mingming Wang

Project administration: Jiayuan Zhang, Linwen Deng, Yao Peng.

Resources: Yao Peng.

Software: Jiayuan Zhang, Dong Wang.

Visualization: Jiayuan Zhang.

Writing original draft: Jiayuan Zhang, Mingming Wang.

Review and editing: Yao Peng, Linwen Deng.

Funding

Not applicable.

Availability of data and materials**

The datasets generated and/or analyzed during the current study are derived from public databases and published literature. Detailed information can be found in the "GWAS sources" section of the manuscript.

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Alzheimer's disease and antibody-mediated immune responses to infectious diseases agents: A mendelian randomization study

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Abstract

Background

Methods

Results

Conclusion

Figures

1. Introduction

2. Method

2.1. Study design

2.2. GWAS sources

2.3. The selection of IVs

2.4. Statistical analysis

3. Results

3.1. Causal impact of antibodies on AD

3.2. Sensitivity analysis

3.3. Influence of AD on 46 antibodies

4. Discussion

4.1.1. Antibody-mediated immune responses to polyomavirus infections reduced AD Risk

4.1.2. Antibody-mediated immune responses to varicella zoster virus infections reduced AD Risk

4.1.3. Antibody-mediated immune responses to Toxoplasma gondii infections increased AD Risk

4.1.4. Antibody-mediated immune responses to Epstein-Barr virus infections increased AD Risk

4.1.5. Limitation

5. Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1