Cortical structure and the risk for Alzheimer's disease: a bidirectional Mendelian randomization study.
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SUBMITTER: Wu BS
PROVIDER: S-EPMC8443658 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionObservational studies have indicated widespread comorbidity of white matter (WM) lesions and Alzheimer's disease (AD) in the elderly, but the causality and direction of their relationship remained unclear. Our study aims to examine the bidirectional causal relationship between WM change and AD using a genetically informed method.MethodsWe performed a bidirectional two-sample mendelian randomization (MR) study to investigate the correlation of three WM phenotypes-white matter hyperintensities (WMH, N = 18,381), fractional anisotropy (FA, N = 17,673), and mean diffusivity (MD, N = 17,467)-with AD (N = 63,926) using summary statistics from genome-wide association studies (GWAS). The inverse variance weighted method (IVW) was used to evaluate the causal estimate and alternative methods to test the heterogeneity, horizontal pleiotropy, and outliers.ResultsThere was no significant causal evidence of WM MRI markers on AD across all MR methods. We identified significant evidence of causal effects of AD on the risk of WMH (OR 1.06, 95% CI 1.03-1.10, p < 0.01). The same direction of effects was observed in MR-Egger, weighted median, and weighted mode analysis. Besides, we also observed a risk causal relationship between AD with MD in MR-Egger, weighted median, and weighted mode-based methods (MR-Egger OR 1.38, 95% CI 1.07-1.79, p = 0.02; weighted median OR 1.21, 95% CI 1.02-1.45, p = 0.03; weighted mode-based OR 1.32, 95% CI 1.14-1.53, p < 0.01). However, the general significance of the causal effect of AD on WMH and MD disappeared when we removed the single nucleotide polymorphisms (SNPs) near the APOE regions, revealing that the ability of AD to increase the risk of white matter damage might be mediated by APOE to some extent. Unfortunately, we did not observe significant causal evidence of AD on FA across all MR analyses.ConclusionsIn this bidirectional MR study, we did not observe that WM injuries were associated with a higher risk of AD. Likewise, genetically predicted AD did not result in a causal effect on white matter damage. However, our research revealed that underlying mechanisms linking AD and white matter lesions might be related to the SNPs near APOE regions.
| S-EPMC9095794 | biostudies-literature
Project description:Alzheimer's disease (AD) manifests with a higher rate of occurrence in women. Previous epidemiological studies have suggested a potential association between AD and gynecological cancers, but the causal relationship between them remains unclear. This study aims to explore the causal link between 12 types of gynecological cancers and AD using a bidirectional Mendelian randomization (MR) approach. We obtained genetic correlation tools for AD using data from the most extensive genome-wide association study. Genetic correlation data for 12 types of gynecological cancers were also sourced from the Finnish Biobank. These cancers include breast cancer (BC), cervical adenocarcinoma (CA), cervical squamous cell carcinoma (CSCC), cervical cancer (CC), endometrial cancer (EC), ovarian endometrioid carcinoma (OEC), ovarian cancer (OC), ovarian serous carcinoma (OSC), breast carcinoma in situ (BCIS), cervical carcinoma in situ (CCIS), endometrial carcinoma in situ (ECIS), and vulvar carcinoma in situ (VCIS). We used the inverse-variance weighted (IVW) model for causal analysis and conducted horizontal pleiotropy tests, heterogeneity tests, MR-PRESSO tests, and leave-one-out analyses to ensure the robustness of our results. We also applied replication analysis and meta-analysis to further validate our experimental results. The study found that EC (P_IVW =0.037, OR [95% CI] = 1.032 [1.002, 1.064]) and CCIS (P_IVW = 0.046, OR [95% CI] = 1.032 [1.011, 1.064]) increase the risk of AD, whereas OC was negatively correlated with AD (P_IVW = 0.016, OR [95% CI] = 0.974[0.954, 0.995]). In reverse MR analysis, AD increased the risk of CC (P_IVW = 0.039, OR [95% CI] = 1.395 [1.017, 1.914]) and VCIS (P_IVW = 0.041, OR [95% CI] = 1.761 [1.027, 2.021]), but was negatively correlated with OEC (P_IVW = 0.034, OR [95% CI] = 0.634 [0.417, 0.966]). Sensitivity analysis results demonstrated robustness. These findings were further substantiated through replication and meta-analyses. Our MR study supports a causal relationship between AD and gynecological cancers. This encourages further research into the incidence of gynecological cancers in female Alzheimer's patients and the active prevention of AD.
| S-EPMC11337634 | biostudies-literature
Project description:BackgroundThere is a complex, bidirectional relationship between Alzheimer's disease (AD) and epilepsy. However, the causality of this association is unclear, as confounders play a role in this association.MethodsWe conducted a Mendelian randomization (MR) study to clarify the causal relationship and direction of epilepsy on AD risk. We used publicly available summary statistics to obtain all genetic datasets for the MR analyses. AD and AD-by-proxy and late-onset AD (LOAD) cohorts were included in our study. The epilepsy cohort comprised all epilepsy, generalized epilepsy, focal epilepsy, and its subtypes, as well as some epilepsy syndromes. Next, we conducted validation using another AD cohort.ResultsTwo correlations between AD and epilepsy using the inverse variance-weighted (IVW) method are as follows: LOAD and focal epilepsy (ORIVW = 1.079, pIVW = .013), focal epilepsy-documented hippocampal sclerosis (HS) and AD (ORIVW = 1.152, pIVW = .017). The causal relationship between epilepsy-documented HS and AD has been validated (ORIVW = 3.994, pIVW = .027).ConclusionsOur MR study provides evidence for a causal relationship between focal epilepsy-documented HS and AD.
| S-EPMC10636418 | biostudies-literature
Project description:Increased expression of CD33 in the brain has been suggested to be associated with increased amyloid plaque burden, while the peripheral level of CD33 in Alzheimer's disease (AD) patients and its role in AD remain unclear. The current study aimed to systematically explore the bidirectional relationship between peripheral CD33 and AD. Genome-wide association study (GWAS) datasets of AD (Ncases: 21982; Ncontrols: 41944), blood CD33 mRNA level, the plasma CD33 protein level, and CD33 expression on immune-cell subtypes were obtained from GWASs conducted in the European population. Eligible IVs were extracted from the GWASs. MR estimates were calculated by inverse-variance weighting (IVW) and other sensitivity analyses. The main statistical analyses were conducted using TwoSampleMR (v.0.5.5) in R package (V.4.1.2).In the forward MR analysis (CD33 as exposure and AD as outcome), the IVW results indicated that elevated blood CD33 mRNA level (OR [95% CI] = 1.156[1.080, 1.238], p = 3.25e-05), elevated serum CD33 protein level (OR [95% CI] = 1.08 [1.031, 1.139], p = 1.6e-03) and increased CD33's expression on immune cell subtypes (p < 0.05) were all leading to a higher risk of AD. And sensitivity analyses supported these findings. While the reverse MR analysis (AD as exposure and CD33 as outcome) indicated that AD was not leading to the elevation of CD33's protein level in the blood (p > 0.05). In conclusion, our results indicated that elevated peripheral expression of CD33 was causal to the development of AD. Future studies are needed to work on developing CD33 as a biomarker and therapeutic target in AD.
| S-EPMC9529877 | biostudies-literature
Project description:BackgroundPrevious observational studies have reported that delirium has an association with an increased risk of Alzheimer's disease (AD), and that patients with AD have a higher risk of developing delirium. However, due to the limitations of observational study, it is challenging to confirm whether delirium has a causal effect on AD or reverse causation exists.MethodsA bidirectional two-sample Mendelian randomization (MR) was performed to investigate the relationship between delirium and AD. Summary statistics from genome-wide association studies of delirium and AD phenotypes were utilized. Inverse-variance weighted (IVW) method was used as the main analysis approach, and additional analyses were performed using MR Egger, weighted median, simple mode and weighted mode to ensure result accuracy. Heterogeneity and horizontal pleiotropy were assessed using Cochran's Q statistics and MR Egger intercept, separately.ResultsThe MR analyses showed that genetically predicted delirium was not associated with AD (IVW: odds ratio [OR] 0.98, 95% CI 0.91-1.05, P = 0.544; MR Egger: OR 0.98, 95% CI 0.83-1.15, P = 0.780; weighted median: OR 0.96, 95% CI 0.88-1.05, P = 0.323; simple mode: OR 0.91, 95% CI 0.80-1.04, P = 0.212; weighted mode: OR 0.93, 95% CI 0.83-1.05, P = 0.277). However, in the reverse direction, AD was associated with delirium (IVW: OR 1.32, 95% CI 1.13-1.54, P = 3.91E-04; MR Egger: OR 1.42, 95% CI 1.02-1.98, P = 5.60E-02; Weighted median: OR 1.39, 95% CI 1.18-1.63, P = 8.22E-05; Simple mode: OR 1.41, 95% CI 1.10-1.80, P = 1.41E-02; Weighted mode: OR 1.39, 95% CI 1.16-1.67, P = 3.23E-03).ConclusionBased on the results of our MR study, there is no bidirectional causality between delirium and AD, delirium is not associated with an increased risk of AD, while genetically predicted AD is a potential causal risk factor for delirium.
| S-EPMC10405368 | biostudies-literature
Project description:BackgroundMany observational studies have investigated the link between the gut microbiota and Alzheimer's disease (AD), but the causality remains uncertain.ObjectiveThis study aimed to evaluate the causal impact of gut microbiota on AD.MethodsA two-sample Mendelian randomization (MR) study was conducted employing summary data. Summary statistics for AD were from the latest genome-wide association study (cases and proxy cases: 85,934; controls: 401,577). Summary data for gut microbiota were acquired from MiBioGen consortium. Causal effect estimations primarily relied on the inverse variance weighting method along with the sensitivity analyses for testing for pleiotropy and heterogeneity. Additionally, reverse MR analyses were performed to examine potential reverse causality.ResultsSeven gut microbiota were identified as associated with AD risk. Order Selenomonadales (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.03-1.24, p = 0.01), Family Pasteurellaceae (OR 1.07, 95% CI 1.01-1.13, p = 0.01), and Genus Methanobrevibacter (OR 1.07, 95% CI 1.00-1.13, p = 0.04) were correlated with an elevated likelihood of AD, while Class Mollicutes (OR 0.87, 95% CI 0.79-0.95, p = 0.00), Genus Ruminiclostridium9 (OR 0.87, 95% CI 0.78-0.97, p = 0.01), Genus Clostridiuminnocuumgroup (OR 0.94, 95% CI 0.89-0.99, p = 0.03), and Genus Eggerthella (OR 0.94, 95% CI 0.89-1.00, p = 0.04) exerted beneficial impact in mitigating AD. No statistically significant reverse causality was found between AD and each of these seven specific gut microbiota species.ConclusionsThis study unveiled a causal link between certain gut microbiota and AD, offering new insights for advancing clinical treatments.
| S-EPMC11305842 | biostudies-literature
Project description:Observational studies suggest that cardiovascular disease (CVD) increases the risk of developing Alzheimer's disease (AD). However, the causal relationship between the two is not clear. This study applied a two-sample bidirectional Mendelian randomization method to explore the causal relationship between CVD and AD. Genome-wide association study (GWAS) data from 46 datasets of European populations (21,982 cases of AD and 41,944 controls) were utilized to obtain genetic instrumental variables for AD. In addition, genetic instrumental variables for atrial fibrillation (AF), heart failure (HF), myocardial infarction (MI), coronary heart disease (CHD), angina pectoris (AP), and ischemic stroke (IS) (including large-artery atherosclerotic stroke [LAS] and cardioembolic stroke [CES]) were selected from GWAS data of European populations (P < 5E-8). The inverse variance weighting method was employed as the major Mendelian randomization analysis method. Genetically predicted AD odds ratios (OR) (1.06) (95% CI: 1.02-1.10, P = 0.003) were linked to higher AP analysis. A higher genetically predicted OR for CES (0.9) (95% CI 0.82-0.99, P = 0.02) was linked to a decreased AD risk. This Mendelian randomized study identified AD as a risk factor for AP. In addition, CES was related to a reduced incidence of AD. Therefore, these modifiable risk factors are crucial targets for preventing and treating AD.
| S-EPMC10522384 | biostudies-literature
Project description:Recent experimental studies indicated that a periodontitis-causing bacterium might be a causal factor for Alzheimer's disease (AD). We applied a two-sample Mendelian randomization (MR) approach to examine the potential causal relationship between chronic periodontitis and AD bidirectionally in the population of European ancestry. We used publicly available data of genome-wide association studies (GWAS) on periodontitis and AD. Five single-nucleotide polymorphisms (SNPs) were used as instrumental variables for periodontitis. For the MR analysis of periodontitis on risk of AD, the causal odds ratio (OR) and 95% confidence interval (CI) were derived from the GWAS of periodontitis (4,924 cases vs. 7,301 controls) and from the GWAS of AD (21,982 cases vs. 41,944 controls). Seven non-overlapping SNPs from another latest GWAS of periodontitis was used to validate the above association. Twenty SNPs were used as instrumental variables for AD. For the MR analysis of liability to AD on risk of periodontitis, the causal OR was derived from the GWAS of AD including 30,344 cases and 52,427 controls and from the GWAS of periodontitis consisted of 12,289 cases and 22,326 controls. We employed multiple methods of MR. Using the five SNPs as instruments of periodontitis, there was suggestive evidence of genetically predicted periodontitis being associated with a higher risk of AD (OR 1.10, 95% CI 1.02 to 1.19, P = 0.02). However, this association was not verified using the seven independent SNPs (OR 0.97, 95% CI 0.87 to 1.08, P = 0.59). There was no association of genetically predicted AD with the risk of periodontitis (OR 1.00, 95% CI 0.96 to 1.04, P = 0.85). In summary, we did not find convincing evidence to support periodontitis being a causal factor for the development of AD. There was also limited evidence to suggest genetic liability to AD being associated with the risk of periodontitis.
| S-EPMC6980529 | biostudies-literature
Project description:Background: Colorectal cancer and Alzheimer's disease are both common life-threatening diseases in the elderly population. Some studies suggest a possible inverse relationship between colorectal cancer and Alzheimer's disease, but real-world research is subject to many biases. We hope to clarify the causal relationship between the two through a bidirectional two-sample Mendelian randomization study. Methods: In our study, we used genetic summary data from large-scale genome-wide association studies to investigate the relationship between colorectal cancer and Alzheimer's disease. Our primary analysis employed the inverse-variance weighted method and we also used complementary techniques, including MR-Egger, weighted median estimator, and Maximum likelihood. We applied simex adjustment to the MR-Egger results. We also utilized the MRlap package to detect potential sample overlap and its impact on the bias of the results. In addition, we performed several sensitivity and heterogeneity analyses, to ensure the reliability of our results. Results: The combined effect size results of the inverse-variance weighted method indicate that colorectal cancer may decrease the incidence of Alzheimer's disease, with an odds ratio (OR) of 0.846 (95% CI: 0.762-0.929). Similar results were observed using other methods such as MR-Egger, weighted median estimator, and Maximum likelihood. On the other hand, Alzheimer's disease may slightly increase the incidence of colorectal cancer, with an OR of 1.014 (95% CI: 1.001-1.027). However, the results of one subgroup were not significant, and the results from MRlap indicated that sample overlap introduced bias into the results. Therefore, the results of the reverse validation are not reliable. The F-statistic for all SNPs was greater than 20. Four SNPs related to the outcome were excluded using Phenoscanner website but the adjustment did not affect the overall direction of the results. The results of these statistics were further validated by MR-PRESSO, funnel plots, leave-one-out analyses, Cochran's Q, demonstrating the reliability of the findings. Conclusion: According to the findings of this Mendelian randomization study, there appears to be a causal association between colorectal cancer and Alzheimer's disease. These results could have important implications for clinical practice in terms of how colorectal cancer and Alzheimer's disease are treated. To better understand the relationship between these two diseases, more research and screening are needed in clinical settings.
| S-EPMC10797121 | biostudies-literature
Project description:Background: Traditional observational studies have demonstrated an association between heart failure and Alzheimer's disease. The strengths of observational studies lie in their speed of implementation, cost, and applicability to rare diseases. However, observational studies have several limitations, such as uncontrollable confounders. Therefore, we employed Mendelian randomization of genetic variants to evaluate the causal relationships existing between AD and HF, which can avoid these limitations. Materials and Methods: A two-sample bidirectional MR analysis was employed. All datasets were results from the UK's Medical Research Council Integrative Epidemiology Unit genome-wide association study database, and we conducted a series of control steps to select the most suitable single-nucleotide polymorphisms for MR analysis, for which five primary methods are offered. We reversed the functions of exposure and outcomes to explore the causal direction of HF and AD. Sensitivity analysis was used to conduct several tests to avoid heterogeneity and pleiotropic bias in the MR results. Results: Our MR studies did not support a meaningful causal relationship between AD on HF (MR-Egger, p = 0.634 > 0.05; weighted median (WM), p = 0.337 > 0.05; inverse variance weighted (IVW), p = 0.471 > 0.05; simple mode, p = 0.454 > 0.05; weighted mode, p = 0.401 > 0.05). At the same time, we did not find a significant causal relationship between HF and AD with four of the methods (MR-Egger, p = 0.195 > 0.05; IVW, p = 0.0879 > 0.05; simple mode, p = 0.170 > 0.05; weighted mode, p = 0.110 > 0.05), but the WM method indicated a significant effect of HF on AD (p = 0.025 < 0.05). Because the statistical powers of IVW and MR-Egger are more than that of WM, we think that there is no causal effect of HF on AD. Sensitivity analysis and horizontal pleiotropy were not detected in the MR analysis. Conclusion: Our results did not provide significant evidence indicating any causal relationships between HF and AD in the European population. Therefore, more large-scale datasets or datasets related to similar factors are expected for further MR analysis.
| S-EPMC8787319 | biostudies-literature