Fibrinogen in Alzheimer's Disease, Parkinson's Disease and Lewy Body Dementia: A Mendelian Randomization Study.
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ABSTRACT:
SUBMITTER: Zhang H
PROVIDER: S-EPMC9300417 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Alzheimer's disease (AD) and Parkinson's disease (PD) are the top two common neurodegenerative diseases in elderly. Recent studies found the ?-synuclein have a key role in AD. Although many clinical and pathological features between AD and PD are shared, the genetic association between them remains unclear, especially whether ?-synuclein in PD genetically alters AD risk. RESULTS:We did not obtain any significant result (OR?=?0.918, 95% CI: 0.782-1.076, P?=?0.291) in MR analysis between PD and AD risk. In MR between ?-synuclein in PD with AD risk, we only extracted rs356182 as the IV through a strict screening process. The result indicated a significant association based on IVW method (OR?=?0.638, 95% CI: 0.485-0.838, P?=?1.20E-03). In order to examine the robustness of the IVW method, we used other three complementary analytical methods and also obtained consistent results. CONCLUSION:The overall PD genetic risk factors did not predict AD risk, but the ?-synuclein susceptibility genetic variants in PD reduce the AD risk. We believe that our findings may help to understand the association between them, which may be useful for future genetic studies for both diseases.
| S-EPMC6311900 | biostudies-literature
Project description:Obesity has been reported to be related to memory impairment and decline in cognitive function, possibly further leading to the development of Alzheimer's disease (AD). However, observational studies revealed both negative and positive associations between body shape (BS) and AD, thereby making it difficult to confirm causality due to residual confounds and reverse causation. Thus, using genome-wide association study summary data, two-sample Mendelian randomization (MR) analyses were applied to identify whether there exists a causal association between BS and AD. BS was measured using anthropometric traits (ATs) in this study, including body mass index (BMI), waist-to-hip ratio (WHR), waist-to-hip ratio adjusted by body mass index (WHRadjBMI), and waist circumference (WC). The associations of single nucleotide polymorphisms (SNP) with each AT and AD were obtained separately from aggregated data from the Genetic Investigation of Anthropometric Traits (GIANT) consortium and International Genomics of Alzheimer's Project (IGAP) summary data (17,008 cases with AD and 37,154 controls). An inverse-variance weighted method was applied to obtain the overall causal estimate for multiple instrumental SNPs. The odds ratio (OR) [95% confidence interval (CI)] for AD risk per 1-SD difference in BMI was 1.04 (0.88, 1.23), in WHR was 1.01 (0.77, 1.33), in WHRadjBMI was 1.12 (0.89, 1.41), and in WC was 1.02 (0.82, 1.27). Furthermore, simulation analyses of survivor bias indicated the overall causal effect of BMI on risk of AD was not biased. In conclusion, the evidence from MR analyses showed no casual effect of BS on AD risk, which is inconsistent with the results from previous observational studies. The biological mechanism underlying the findings warrants further study.
| S-EPMC6795688 | biostudies-literature
Project description:As the differential diagnosis of dementias based on established clinical criteria is often difficult, biomarkers for applicable diagnostic testing are currently under intensive investigation. Amyloid plaques deposited in the brain of patients suffering from Alzheimer's disease, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) mainly consist of carboxy-terminally elongated forms of amyloid-beta (Abeta) peptides, such as Abeta1-42. Absolute Abeta1-42 levels in CSF have shown diagnostic value for the diagnosis of Alzheimer's disease, but the discrimination among Alzheimer's disease, DLB and PDD was poor. A recently established quantitative urea-based Abeta-sodium-dodecylsulphate-polyacrylamide-gel-electrophoresis with Western immunoblot (Abeta-SDS-PAGE/immunoblot) revealed a highly conserved Abeta peptide pattern of the carboxy-terminally truncated Abeta peptides 1-37, 1-38, 1-39 in addition to 1-40 and 1-42 in human CSF. We used the Abeta-SDS-PAGE/immunoblot to investigate the CSF of 23 patients with Alzheimer's disease, 21 with DLB, 21 with PDD and 23 non-demented disease controls (NDC) for disease-specific alterations of the Abeta peptide patterns in its absolute and relative quantities. The diagnostic groups were matched for age and severity of dementia. The present study is the first attempt to evaluate the meaning of Abeta peptide patterns in CSF for differential diagnosis of the three neurodegenerative diseases--Alzheimer's disease, DLB and PDD. The Abeta peptide patterns displayed disease-specific variations and the ratio of the differentially altered Abeta1-42 to the Abeta1-37 levels subsequently discriminated all diagnostic groups from each other at a highly significant level, except DLB from PDD. Additionally, a novel peptide with Abeta-like immunoreactivity was observed constantly in the CSF of all 88 investigated patients. The pronounced percentage increase of this peptide in DLB allowed a highly significant discrimination from PDD. Using a cut-off point of 0.954%, this marker yielded a diagnostic sensitivity and specificity of 81 and 71%, respectively. From several lines of indication, we consider this peptide to represent an oxidized alpha-helical form of Abeta1-40 (Abeta1-40*). The increased abundance of Abeta1-40* probably reflects a disease-specific alteration of the Abeta1-40 metabolism in DLB. We conclude that Abeta peptide patterns reflect disease-specific pathophysiological pathways of different dementia syndromes as distinct neurochemical phenotypes. Although Abeta peptide patterns failed to fulfil the requirements for a sole biomarker, their combined evaluation with other biomarkers is promising in neurochemical dementia diagnosis. It is noteworthy that DLB and PDD exhibit distinct clinical temporal courses, despite their similar neuropathological appearance. Their distinct molecular phenotypes support the view of different pathophysiological pathways for each of these neurodegenerative diseases.
| S-EPMC5403412 | biostudies-literature
Project description:Utilizing the publicly available neuroimaging database enabled by Alzheimer's disease Neuroimaging Initiative (ADNI; http://adni.loni.usc.edu/ ), we have compared the performance of automated classification algorithms that differentiate AD vs. normal subjects using Positron Emission Tomography (PET) with fluorodeoxyglucose (FDG). General linear model, scaled subprofile modeling and support vector machines were examined. Among the tested classification methods, support vector machine with Iterative Single Data Algorithm produced the best performance, i.e., sensitivity (0.84)?×?specificity (0.95), by 10-fold cross-validation. We have applied the same classification algorithm to four different datasets from ADNI, Health Science Centre (Winnipeg, Canada), Dong-A University Hospital (Busan, S. Korea) and Asan Medical Centre (Seoul, S. Korea). Our data analyses confirmed that the support vector machine with Iterative Single Data Algorithm showed the best performance in prediction of future development of AD from the prodromal stage (mild cognitive impairment), and that it was also sensitive to other types of dementia such as Parkinson's Disease Dementia and Dementia with Lewy Bodies, and that perfusion imaging using single photon emission computed tomography may achieve a similar accuracy to that of FDG-PET.
| S-EPMC6125295 | biostudies-literature
Project description:Stroke and Alzheimer's disease (AD) are common neurological diseases. Several exiting studies indicated that late onset-AD and ischemic stroke have shared genetic links. Different kinds of stroke have different mechanisms. However, it remains unclear whether there is a causal relationship between different types of strokes, including any stroke (AS), any ischemic stroke (AIS), large-artery atherosclerotic stroke (LAS), and cardio-embolic stroke (CES), and AD. Herein, we conducted several Mendelian randomization (MR) studies to explore genetically causal link of different kinds of strokes and AD. The results for inverse-variance weighted (IVW) meta-analysis (? = -0.039, OR = 0.9618, and P-value = 0.750) and weighted median regression (WMR) (? = -0.156, OR = 0.8556, and P-value = 0.274) demonstrated that AS is not causally associated with AD risk. The result of MR-Egger regression (? = -1.312, P-value = 0.098) and intercept term (P-value = 0.105) illustrated no pleiotropy in this MR study. According to the results for IVW (P-value = 0.305, ? = -0.103, and OR = 0.9021) and WMR (P-value = 0.487, ? = -0.092, and OR = 0.9121) in the MR study between AIS and AD, there is no causal association between AIS and AD risk. In addition, the MR-Egger regression (P-value = 0.290 and ? = -0.512) and intercept term (P-value = 0.387) showed no potential pleiotropy. LAS is not causally associated with AD risk according to the MR results (IVW: P-value = 0.568, ? = 0.037, and OR = 1.0377; WMR: P-value = 0.793, ? = -0.022, and OR = 0.9782). Additionally, the results of MR-Egger regression (P-value = 0.122 and ? = -1.220) and intercept term (P-value = 0.110) showed no potential pleiotropy. Our results [IVW: P-value = 0.245, ? = -0.064, and OR = 0.938; WMR: P-value = 0.331, ? = -0.057, and OR = 0.9446; MR-Egger: P-value = 0.673 and ? = -0.062, and intercept term (P-value = 0.985)] further demonstrated there is no causal link between CES and AD and no pleiotropy in this MR study. In conclusion, different types of stroke, including AS, AIS, LAS, and CES, would not be causally associated with AD risk.
| S-EPMC7371994 | biostudies-literature
Project description:Context:Recently, data on 2,000,000 people established that low body mass index (BMI) is associated with increased risk of dementia. Whether this observational association reflects a causal effect remains to be clarified. Objective:We tested the hypothesis that there is a causal association between low BMI and high risk of Alzheimer's disease. Design, Setting, and Participants:Using a Mendelian randomization approach, we studied 95,578 individuals from the Copenhagen General Population Study (CGPS) with up to 36 years of follow-up and consortia data on 303,958 individuals from the Genetic Investigation of Anthropometric Traits (GIANT) and the International Genomics of Alzheimer's Project (IGAP). Main Outcome Measure:Risk of Alzheimer's disease. Results:The causal odds ratio for a 1-kg/m2 genetically determined lower BMI was 0.98 [95% confidence interval (CI), 0.77 to 1.23] for a weighted allele score in the CGPS. Using 32 BMI-decreasing variants from GIANT and IGAP the causal odds ratio for Alzheimer's disease for a 1-standard deviation (SD) lower genetically determined BMI was 1.02 (95% CI, 0.86 to 1.22). Corresponding observational hazard ratios from the CGPS were 1.07 (95% CI, 1.05 to 1.09) and 1.32 (95% CI, 1.20 to 1.46) for a 1-kg/m2 and a 1-SD lower BMI, respectively. Conclusions:Genetic and hence lifelong low BMI is not associated with increased risk of Alzheimer's disease in the general population. These data suggest that low BMI is not a causal risk factor for Alzheimer's disease and that the corresponding observational association likely is explained by reverse causation or confounding.
| S-EPMC5505195 | biostudies-literature
Project description:Alzheimer's disease (AD) is the most common neurodegenerative disease. In recent years, multiple pathway analyses of AD genome-wide association studies (GWAS) have been conducted, and provided strong support for immune pathways in AD. Rheumatoid arthritis (RA) is a chronic autoimmune disease. It is reported that antirheumatic drugs had protective effect on dementia in RA patients. However, observational studies have reported a controversial inverse relationship between AD and RA. In addition, Mendelian randomization studies have also been performed to evaluate the association of RA with AD. However, these studies reported inconsistent association of RA with AD. Until now, it is still unclear that AD is a causally associated with RA. Here, we performed a Mendelian randomization study to investigate the causal association of AD with RA. We analyzed the large-scale AD GWAS dataset (74,046 individuals) and RA GWAS dataset (58,284 individuals) from the European descent. However, we did not identify any significant association of AD with RA using inverse-variance weighted meta-analysis (IVW), weighted median regression and MR-Egger regression.
| S-EPMC6143656 | biostudies-literature
Project description:Background:Alzheimer's disease is a devastating neurodegenerative disorder. Its worldwide prevalence is over 24 million and is expected to double by 2040. Finding ways to prevent its cognitive decline is urgent. Methods:A two-sample Mendelian randomization study was performed instrumenting glutamine, which is abundant in blood, capable of crossing the blood-brain barrier, and involved in a metabolic cycle with glutamate in the brain. Results:The results reveal a protective effect of circulating glutamine against Alzheimer's disease (inverse-variance weighted method, odds ratio per 1-standard deviation increase in circulating glutamine = 0.83; 95% CI 0.71, 0.97; P = 0.02). Conclusion:These findings lend credence to the emerging story supporting the modifiability of glutamine/glutamate metabolism for the prevention of cognitive decline. More circulating glutamine might mean that more substrate is available during times of stress, acting as a neuroprotectant. Modifications to exogenous glutamine may be worth exploring in future efforts to prevent and/or treat Alzheimer's disease.
| S-EPMC7020919 | biostudies-literature
Project description:Previous observational studies have reported an association between impaired glucose metabolism and Alzheimer's disease. This study aimed to examine the causal association of glycemic traits with Alzheimer's disease. We used a two-sample Mendelian randomization approach to evaluate the causal effect of six glycemic traits (type 2 diabetes, fasting glucose, fasting insulin, hemoglobin A1c, homeostasis model assessment- insulin resistance and HOMA-?-cell function) on Alzheimer's disease. Summary data on the association of single nucleotide polymorphisms with these glycemic traits were obtained from genome-wide association studies of the DIAbetes Genetics Replication And Meta-analysis and Meta-Analyses of Glucose and Insulin-related traits Consortium. Summary data on the association of single nucleotide polymorphisms with Alzheimer's disease were obtained from the International Genomics of Alzheimer's Project. The Mendelian randomization analysis showed that 1-standard deviation higher fasting glucose and lower HOMA-?-cell function (indicating pancreatic ?-cell dysfunction) were causally associated with a substantial increase in risk of Alzheimer's disease (odds ratio=1.33, 95% confidence interval: 1.04-1.68, p=0.02; odds ratio=1.92, 95% confidence interval: 1.15-3.21, p=0.01). However, no significant association was observed for other glycemic traits. This Mendelian randomization analysis provides evidence of causal associations between glycemic traits, especially high fasting glucose and pancreatic ?-cell dysfunction, and high risk of Alzheimer's disease.
| S-EPMC7746331 | biostudies-literature
Project description:BackgroundObservational studies have suggested that herpesvirus infection increased the risk of Alzheimer's disease (AD), but it is unclear whether the association is causal. The aim of the present study is to evaluate the causal relationship between four herpesvirus infections and AD.MethodsWe performed a two-sample Mendelian randomization analysis to investigate association of four active herpesvirus infections with AD using summary statistics from genome-wide association studies. The four herpesvirus infections (i.e., chickenpox, shingles, cold sores, mononucleosis) are caused by varicella-zoster virus, herpes simplex virus type 1, and Epstein-Barr virus (EBV), respectively. A large summary statistics data from International Genomics of Alzheimer's Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was further performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD and 272,244 controls).ResultsWe found evidence of a significant association between mononucleosis (caused by EBV) and risk of AD after false discovery rates (FDR) correction (odds ratio [OR] = 1.634, 95% confidence interval [CI] = 1.092-2.446, P = 0.017, FDR-corrected P = 0.034). It has been verified in validation analysis that mononucleosis is also associated with family history of AD (OR [95% CI] = 1.392 [1.061, 1.826], P = 0.017). Genetically predicted shingles were associated with AD risk (OR [95% CI] = 0.867 [0.784, 0.958], P = 0.005, FDR-corrected P = 0.020), while genetically predicted chickenpox was suggestively associated with increased family history of AD (OR [95% CI] = 1.147 [1.007, 1.307], P = 0.039).ConclusionsOur findings provided evidence supporting a positive relationship between mononucleosis and AD, indicating a causal link between EBV infection and AD. Further elucidations of this association and underlying mechanisms are likely to identify feasible interventions to promote AD prevention.
| S-EPMC8464096 | biostudies-literature