Impact of Serum Calcium Levels on Alzheimer’s Disease: A Mendelian Randomization Study

AbstractIMPORTANCE Alzheimer’s disease (AD) is the leading cause of disability in the elderly. It has been a long time about the calcium hypothesis of AD on the basis of emerging evidence since 1994. However, most studies focused on the association between calcium homeostasis and AD, and concerned the intracellular calcium concentration. Only few studies reported reduced serum calcium levels in AD. Until now, it remains unclear whether serum calcium levels are genetically associated with AD risk.OBJECTIVE To evaluate the genetic association between increased serum calcium levels and AD riskDESIGN, SETTING, AND PARTICIPANTS We performed a Mendelian randomization study to investigate the association of increased serum calcium with AD risk using the genetic variants from the large-scale serum calcium genome-wide association study (GWAS) dataset (N=61,079 individuals of European descent) and the large-scale AD GWAS dataset (N=54,162 individuals including 17,008 AD cases and 37,154 controls of European descent). Inverse-variance weighted meta-analysis (IVW) was used to provide a combined estimate of the genetic association. Meanwhile, we selected the weighted median regression and MR-Egger regression as the complementary analysis methods to examine the robustness of the IVW estimate.EXPOSURES Genetic predisposition to increased serum calcium levelsMAIN OUTCOMES AND MEASURES The risk of AD.RESULTS We selected 6 independent genetic variants influencing serum calcium levels as the instrumental variables. IVW analysis showed that a genetically increased serum calcium level (per 1 standard deviation (SD) increase 0.5-mg/dL) was significantly associated with a reduced AD risk (OR=0.56, 95% CI: 0.34-0.94, P=5.00E-03). Meanwhile, both the weighted median estimate (OR=0.60, 95% CI: 0.34-1.06, P=0.08) and MR-Egger estimate (OR=0.66, 95% CI: 0.26-1.67, P=0.381) were consistent with the IVW estimate in terms of direction and magnitude.CONCLUSIONS AND RELEVANCE We provided evidence that genetically increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be further conducted to assess the effect of serum calcium levels on AD risk, and further clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD.Key PointsQuestion Is there a genetic relationship between elevated serum calcium levels and the risk of Alzheimer’s disease?Findings This Mendelian randomization study showed that the genetically increased serum calcium levels were associated with the reduced risk of Alzheimer’s disease.Meaning These findings provide evidence that genetically increased serum calcium levels could reduce the risk of Alzheimer’s disease.

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An Updated Mendelian Randomization Analysis of the Association Between Serum Calcium Levels and the Risk of Alzheimer’s Disease

Frontiers in Genetics ◽

10.3389/fgene.2021.731391 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuchen Shi ◽

Ruifei Liu ◽

Ying Guo ◽

Qiwei Li ◽

Haichun Zhou ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Serum Calcium ◽

Large Scale ◽

Mendelian Randomization ◽

Causal Association ◽

Cognitively Normal ◽

Gwas Dataset ◽

Weighted Median ◽

Normal Controls

It has been a long time that the relationship between serum calcium levels and Alzheimer’s disease (AD) remains unclear. Until recently, observational studies have evaluated the association between serum calcium levels and the risk of AD, however, reported inconsistent findings. Meanwhile, a Mendelian randomization (MR) study had been conducted to test the causal association between serum calcium levels and AD risk, however, only selected 6 serum calcium SNPs as the instrumental variables. Hence, these findings should be further verified using additional more genetic variants and large-scale genome-wide association study (GWAS) dataset to increase the statistical power. Here, we conduct an updated MR analysis of the causal association between serum calcium levels and the risk of AD using a two-stage design. In discovery stage, we conducted a MR analysis using 14 SNPs from serum calcium GWAS dataset (N = 61,079), and AD GWAS dataset (N = 63,926, 21,982 cases, 41,944 cognitively normal controls). All four MR methods including IVW, weighted median, MR-Egger, and MR-PRESSO showed a reduced trend of AD risk with the increased serum calcium levels. In the replication stage, we performed a MR analysis using 166 SNPs from serum calcium GWAS dataset (N = 305,349), and AD GWAS dataset (N = 63,926, 21,982 cases, 41,944 cognitively normal controls). Only the weighted median indicated that genetically increased serum calcium level was associated with the reduced risk of AD. Hence, additional studies are required to investigate these findings.

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Life Course Adiposity and Alzheimer’s Disease: A Mendelian Randomization Study

Journal of Alzheimer s Disease ◽

10.3233/jad-210345 ◽

2021 ◽

pp. 1-10

Author(s):

Xian Li ◽

Yan Tian ◽

Yu-Xiang Yang ◽

Ya-Hui Ma ◽

Xue-Ning Shen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Life Course ◽

Mendelian Randomization ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association Studies ◽

Fat Percentage ◽

Regression Methods ◽

Weighted Median

Background: Several studies showed that life course adiposity was associated with Alzheimer’s disease (AD). However, the underlying causality remains unclear. Objective: We aimed to examine the causal relationship between life course adiposity and AD using Mendelian randomization (MR) analysis. Methods: Instrumental variants were obtained from large genome-wide association studies (GWAS) for life course adiposity, including birth weight (BW), childhood body mass index (BMI), adult BMI, waist circumference (WC), waist-to-hip ratio (WHR), and body fat percentage (BFP). A meta-analysis of GWAS for AD including 71,880 cases and 383,378 controls was used in this study. MR analyses were performed using inverse variance weighted (IVW), weighted median, and MR-Egger regression methods. We calculated odds ratios (ORs) per genetically predicted standard deviation (1-SD) unit increase in each trait for AD. Results: Genetically predicted 1-SD increase in adult BMI was significantly associated with higher risk of AD (IVW: OR = 1.03, 95% confidence interval [CI] = 1.01–1.05, p = 2.7×10–3) after Bonferroni correction. The weighted median method indicated a significant association between BW and AD (OR = 0.94, 95% CI = 0.90–0.98, p = 1.8×10–3). We also found suggestive associations of AD with WC (IVW: OR = 1.03, 95% CI = 1.00–1.07, p = 0.048) and WHR (weighted median: OR = 1.04, 95% CI = 1.00–1.07, p = 0.029). No association was detected of AD with childhood BMI and BFP. Conclusion: Our study demonstrated that lower BW and higher adult BMI had causal effects on increased AD risk.

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Circulating biomarkers of immunity and inflammation, risk of Alzheimer’s disease, and hippocampal volume: a Mendelian randomization study

Translational Psychiatry ◽

10.1038/s41398-021-01400-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lana Fani ◽

Marios K. Georgakis ◽

M. Arfan Ikram ◽

M. Kamran Ikram ◽

Rainer Malik ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mendelian Randomization ◽

Hippocampal Volume ◽

Cd4 Count ◽

European Ancestry ◽

Monocyte Count ◽

Circulating Biomarkers ◽

Lymphocyte Ratio ◽

Immune Biomarkers

AbstractThe aim of this study was to explore the association between genetically predicted circulating levels of immunity and inflammation, and the risk of Alzheimer’s disease (AD) and hippocampal volume, by conducting a two-sample Mendelian Randomization Study. We identified 12 markers of immune cells and derived ratios (platelet count, eosinophil count, neutrophil count, basophil count, monocyte count, lymphocyte count, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, CD4 count, CD8 count, CD4-to-CD8 ratio, and CD56) and 5 signaling molecules (IL-6, fibrinogen, CRP, and Lp-PLA2 activity and mass) as primary exposures of interest. Other genetically available immune biomarkers with a weaker a priori link to AD were considered secondary exposures. Associations with AD were evaluated in The International Genomics of Alzheimer’s Project (IGAP) GWAS dataset (21,982 cases; 41,944 controls of European ancestry). For hippocampal volume, we extracted data from a GWAS meta-analysis on 33,536 participants of European ancestry. None of the primary or secondary exposures showed statistically significant associations with AD or with hippocampal volume following P-value correction for multiple comparisons using false discovery rate < 5% (Q-value < 0.05). CD4 count showed the strongest suggestive association with AD (odds ratio 1.32, P < 0.01, Q > 0.05). There was evidence for heterogeneity in the MR inverse variance-weighted meta-analyses as measured by Cochran Q, and weighted median and weighted mode for multiple exposures. Further cluster analyses did not reveal clusters of variants that could influence the risk factor in distinct ways. This study suggests that genetically predicted circulating biomarkers of immunity and inflammation are not associated with AD risk or hippocampal volume. Future studies should assess competing risk, explore in more depth the role of adaptive immunity in AD, in particular T cells and the CD4 subtype, and confirm these findings in other ethnicities.

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Causal Association Between Heart Failure and Alzheimer’s Disease: A Two-Sample Bidirectional Mendelian Randomization Study

Frontiers in Genetics ◽

10.3389/fgene.2021.772343 ◽

2022 ◽

Vol 12 ◽

Author(s):

Chenglin Duan ◽

Jingjing Shi ◽

Guozhen Yuan ◽

Xintian Shou ◽

Ting Chen ◽

...

Keyword(s):

Heart Failure ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sensitivity Analysis ◽

Causal Relationship ◽

Observational Studies ◽

Mendelian Randomization ◽

Causal Effect ◽

Causal Relationships ◽

Simple Mode

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.

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Education, intelligence and Alzheimer’s disease: Evidence from a multivariable two-sample Mendelian randomization study

10.1101/401042 ◽

2018 ◽

Cited By ~ 13

Author(s):

Emma L Anderson ◽

Laura D Howe ◽

Kaitlin H Wade ◽

Yoav Ben-Shlomo ◽

W. David Hill ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Educational Attainment ◽

Mendelian Randomization ◽

Causal Effect ◽

Univariate Analysis ◽

Causal Effects ◽

Training Interventions ◽

Bidirectional Relationship ◽

Years Of Schooling

AbstractObjectivesTo examine whether educational attainment and intelligence have causal effects on risk of Alzheimer’s disease (AD), independently of each other.DesignTwo-sample univariable and multivariable Mendelian Randomization (MR) to estimate the causal effects of education on intelligence and vice versa, and the total and independent causal effects of both education and intelligence on risk of AD.Participants17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer’s Project (IGAP) consortiumMain outcome measureOdds ratio of AD per standardised deviation increase in years of schooling and intelligenceResultsThere was strong evidence of a causal, bidirectional relationship between intelligence and educational attainment, with the magnitude of effect being similar in both directions. Similar overall effects were observed for both educational attainment and intelligence on AD risk in the univariable MR analysis; with each SD increase in years of schooling and intelligence, odds of AD were, on average, 37% (95% CI: 23% to 49%) and 35% (95% CI: 25% to 43%) lower, respectively. There was little evidence from the multivariable MR analysis that educational attainment affected AD risk once intelligence was taken into account, but intelligence affected AD risk independently of educational attainment to a similar magnitude observed in the univariate analysis.ConclusionsThere is robust evidence for an independent, causal effect of intelligence in lowering AD risk, potentially supporting a role for cognitive training interventions to improve aspects of intelligence. However, given the observed causal effect of educational attainment on intelligence, there may also be support for policies aimed at increasing length of schooling to lower incidence of AD.

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