scholarly journals Causal effects of circulating cytokine concentrations on risk of Alzheimer’s disease: A bidirectional two-sample Mendelian randomization study

2020 ◽  
Author(s):  
Panagiota Pagoni ◽  
Laura D Howe ◽  
George Davey Smith ◽  
Yoav Ben-Shlomo ◽  
Evie Stergiakouli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Causal Effect ◽  
Causal Effects ◽  
Causal Role ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Weak Evidence ◽  
Increased Risk

ABSTRACTBackgroundThere is considerable interest in the role of neuroinflammation in the pathogenesis of Alzheimer’s disease. Evidence from observational studies suggests an association between cytokine concentrations and Alzheimer’s disease. However, establishing a causal role of cytokine concentrations on risk of Alzheimer’s disease is challenging due to bias from reverse causation and residual confounding.MethodsWe used two-sample MR to explore causal effects of circulating cytokine concentrations on Alzheimer’s disease and vice versa, employing genetic variants associated with cytokine concentrations (N=8,293) and Alzheimer’s disease (71,880 cases / 383,378 controls) from the largest non-overlapping genome-wide association studies (GWAS) of European ancestry.ResultsThere was weak evidence to suggest that 1 standard deviation (SD) increase in levels of CTACK (CCL27) (OR= 1.09 95%CI: 1.01 to 1.19, p=0.03) increased risk of Alzheimer’s disease. There was also weak evidence of a causal effect of 1 SD increase in levels of MIP-1b (CCL4) (OR=1.04 95%CI: 0.99 to 1.09, p=0.08), Eotaxin (OR=1.08 95%CI: 0.99 to 1.17, p =0.10), GROa (CXCL1) (OR=1.04 95%CI: 0.99 to 1.10, p=0.15), MIG (CXCL9) (OR=1.17 95%CI: 0.97 to 1.41, p=0.10), IL-8 (Wald Ratio: OR=1.21 95%CI: 0.97 to 1.51, p=0.09) and IL-2 (Wald Ratio: OR=1.21 95%CI: 0.94 to 1.56, p=0.14) on greater risk of Alzheimer’s disease. There was little evidence of a causal effect of genetic liability to Alzheimer’s disease on circulating cytokine concentrations.ConclusionsOur study provides some evidence supporting a causal role of cytokines in the pathogenesis of Alzheimer’s disease. However, more studies are needed to elucidate the specific mechanistic pathways via which cytokines alter the risk of Alzheimer’s disease.

scholarly journals Polymorphisms inHSD17B1: Early Onset and Increased Risk of Alzheimer’s Disease in Women with Down Syndrome

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Joseph H. Lee ◽  
Susan Gurney ◽  
Deborah Pang ◽  
Alexis Temkin ◽  
Naeun Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Age At Onset ◽  
Nucleotide Polymorphisms ◽  
Risk Alleles ◽  
Increased Risk ◽  
Estrogen Activity ◽  
Intron 4

Background/Aims. Genetic variants that affect estrogen activity may influence the risk of Alzheimer's disease (AD). In women with Down syndrome, we examined the relation of polymorphisms in hydroxysteroid-17beta-dehydrogenase (HSD17B1) to age at onset and risk of AD.HSD17B1encodes the enzyme 17β-hydroxysteroid dehydrogenase (HSD1), which catalyzes the conversion of estrone to estradiol.Methods. Two hundred and thirty-eight women with DS, nondemented at baseline, 31–78 years of age, were followed at 14–18-month intervals for 4.5 years. Women were genotyped for 5 haplotype-tagging single-nucleotide polymorphisms (SNPs) in theHSD17B1gene region, and their association with incident AD was examined.Results. Age at onset was earlier, and risk of AD was elevated from two- to threefold among women homozygous for the minor allele at 3 SNPs in intron 4 (rs676387), exon 6 (rs605059), and exon 4 inCOASY(rs598126). Carriers of the haplotype TCC, based on the risk alleles for these three SNPs, had an almost twofold increased risk of developing AD (hazard ratio = 1.8, 95% CI, 1.1–3.1).Conclusion. These findings support experimental and clinical studies of the neuroprotective role of estrogen.

scholarly journals Genetic Variability in Molecular Pathways Implicated in Alzheimer's Disease: A Comprehensive Review

2021 ◽  
Vol 13 ◽  
Author(s):  
David Vogrinc ◽  
Katja Goričar ◽  
Vita Dolžan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Age Of Onset ◽  
Association Studies ◽  
The Elderly ◽  
Gene Clustering ◽  
Molecular Pathways ◽  
Genome Wide Association Studies ◽  
Cellular Processes ◽  
Increased Risk

Alzheimer's disease (AD) is a complex neurodegenerative disease, affecting a significant part of the population. The majority of AD cases occur in the elderly with a typical age of onset of the disease above 65 years. AD presents a major burden for the healthcare system and since population is rapidly aging, the burden of the disease will increase in the future. However, no effective drug treatment for a full-blown disease has been developed to date. The genetic background of AD is extensively studied; numerous genome-wide association studies (GWAS) identified significant genes associated with increased risk of AD development. This review summarizes more than 100 risk loci. Many of them may serve as biomarkers of AD progression, even in the preclinical stage of the disease. Furthermore, we used GWAS data to identify key pathways of AD pathogenesis: cellular processes, metabolic processes, biological regulation, localization, transport, regulation of cellular processes, and neurological system processes. Gene clustering into molecular pathways can provide background for identification of novel molecular targets and may support the development of tailored and personalized treatment of AD.

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

2018 ◽  
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.

Genetic evidence supporting a causal role of depression on Alzheimer’s disease

2021 ◽  
Author(s):  
Nadia V. Harerimana ◽  
Yue Liu ◽  
Ekaterina S. Gerasimov ◽  
Duc Duong ◽  
Thomas G. Beach ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Evidence ◽  
Causal Role

scholarly journals Exploring the causal effects of genetic liability to ADHD and Autism on Alzheimer’s disease

2020 ◽  
Author(s):  
Panagiota Pagoni ◽  
Christina Dardani ◽  
Beate Leppert ◽  
Roxanna Korologou-Linden ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Educational Attainment ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Autism Spectrum ◽  
Causal Effects ◽  
Direct Effects ◽  
Limited Evidence ◽  
Genetic Liability

ABSTRACTBackgroundThere are very few studies investigating possible links between Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD) and Alzheimer’s disease and these have been limited by small sample sizes, diagnostic and recall bias. However, neurocognitive deficits affecting educational attainment in individuals with ADHD could be risk factors for Alzheimer’s later in life while hyper plasticity of the brain in ASD and strong positive genetic correlations of ASD with IQ and educational attainment could be protective against Alzheimer’s.MethodsWe estimated the bidirectional total causal effects of genetic liability to ADHD and ASD on Alzheimer’s disease through two-sample Mendelian randomization. We investigated their direct effects, independent of educational attainment and IQ, through Multivariable Mendelian randomization.ResultsThere was limited evidence to suggest that genetic liability to ADHD (OR=1.00, 95% CI: 0.98 to 1.02, p=0.39) or ASD (OR=0.99, 95% CI: 0.97 to 1.01, p=0.70) was associated with risk of Alzheimer’s disease. Similar causal effect estimates were identified when the direct effects, independent of educational attainment (ADHD: OR=1.00, 95% CI: 0.99 to 1.01, p=0.07; ASD: OR=0.99, 95% CI: 0.98 to 1.00, p=0.28) and IQ (ADHD: OR=1.00, 95% CI: 0.99 to 1.02. p=0.29; ASD: OR=0.99, 95% CI: 0.98 to 1.01, p=0.99), were assessed. Finally, genetic liability to Alzheimer’s disease was not found to have a causal effect on risk of ADHD or ASD (ADHD: OR=1.12, 95% CI: 0.86 to 1.44, p=0.37; ASD: OR=1.19, 95% CI: 0.94 to 1.51, p=0.14).ConclusionsIn the first study to date investigating the causal associations between genetic liability to ADHD, ASD and Alzheimer’s, within an MR framework, we found limited evidence to suggest a causal effect. It is important to encourage future research using ADHD and ASD specific subtype data, as well as longitudinal data in order to further elucidate any associations between these conditions.

scholarly journals Growth Differentiation Factor 15 Is Associated With Alzheimer’s Disease Risk

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng-Fei Wu ◽  
Xing-Hao Zhang ◽  
Ping Zhou ◽  
Rui Yin ◽  
Xiao-Ting Zhou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Reverse Direction ◽  
Genome Wide Association Studies ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor

BackgroundPrevious observational studies have suggested that associations exist between growth differentiation factor 15 (GDF-15) and neurodegenerative diseases. We aimed to investigate the causal relationships between GDF-15 and Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).MethodsUsing summary-level datasets from genome-wide association studies of European ancestry, we performed a two-sample Mendelian randomization (MR) study. Genetic variants significantly associated (p < 5 × 10–8) with GDF-15 were selected as instrumental variables (n = 5). An inverse-variance weighted method was implemented as the primary MR approach, while weighted median, MR–Egger, leave-one-out analysis, and Cochran’s Q-test were conducted as sensitivity analyses. All analyses were performed using R 3.6.1 with relevant packages.ResultsMR provided evidence for the association of elevated GDF-15 levels with a higher risk of AD (odds ratio = 1.14; 95% confidence interval, 1.04–1.24; p = 0.004). In the reverse direction, Mendelian randomization suggested no causal effect of genetically proxied risk of AD on circulating GDF-15 (p = 0.450). The causal effects of GDF-15 on PD (p = 0.597) or ALS (p = 0.120) were not identified, and the MR results likewise did not support the association of genetic liability to PD or ALS with genetically predicted levels of GDF-15. No evident heterogeneity or horizontal pleiotropy was revealed by multiple sensitivity analyses.ConclusionWe highlighted the role of GDF-15 in AD as altogether a promising diagnostic marker and a therapeutic target.

scholarly journals PVRL2 rs6859 Modifies the Effect of Triglyceride on Progression of Mild Cognitive Impairment: The Shanghai Aging Study

2020 ◽  
Author(s):  
Ruru Wang ◽  
Ding Ding ◽  
Abuduaili Atibaike ◽  
Jianxiong Xi ◽  
Qianhua Zhao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cox Model ◽  
Association Studies ◽  
Interactive Effect ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
Aging Study

Abstract Background Mild cognitive impairment (MCI) is an intermediate stage between normal cognition and Alzheimer’s disease (AD). Genome-wide association studies (GWAS) have identified many AD-risk variants and indicated the important role of lipid metabolism pathway in AD progression. This study aimed to investigate the effects of triglyceride (TG) and genetic risk factors on progression from MCI to AD (MCI-AD progression).Methods The current study sample comprised of 305 MCI subjects aged 50 and over who were prospectively followed up for average 4.5 years in a sub-cohort of the Shanghai Aging Study. A consensus diagnosis of incident AD was conducted according to Diagnostic and Statistical Manual of Mental Disorders-IV and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria. Fasting blood samples were obtained at baseline for analyzing serum TG. Single nucleotide polymorphisms (SNPs) genotyping was performed using a MassARRAY system. The effect of TG, genetic variants and their interaction on MCI-AD progression were analyzed using Cox proportional hazards regression model.Results During a mean (±SD) follow-up period of 4.5±1.3 y, 58 subjects developed incident AD. The SNP, rs6859 in the Poliovirus Receptor–Related 2 (PVRL2) gene, was significantly associated with incident AD (false discovery rate (FDR)-adjusted P = 0.018). In multivariate cox model, the PVRL2 rs6859 AG, AA and AG+AA genotypes were associated with significantly increased incident AD, compared with the GG genotype (hazard ratio [HR] = 2.29, P = 0.029, and HR = 2.92, P = 0.013, and HR = 2.47, P =0.012, respectively). In PVRL2 rs6859 AG/AA carriers, higher ln TG was significantly associated with increased risk of incident AD (adjusted HR =2.64, P = 0.034). Ln TG and PVRL2 rs6859 had interactive effect on the MCI-AD progression (P Ln TG × rs6859 = 0.001). Conclusion The present study indicated that PVRL2 rs6859 modified the effect of TG on MCI-AD progression. Precision prevention in MCI population based on genetic information should be considered to avoid progression to AD.

scholarly journals Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits

2020 ◽  
Author(s):  
William Paul Bone ◽  
Katherine M Siewert ◽  
Anupama Jha ◽  
Derek Klarin ◽  
Scott M Damrauer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Low Frequency ◽  
Tissue Expression ◽  
Genome Wide Association Studies ◽  
Frequency Coding ◽  
Increased Risk ◽  
Hypertensive Drug ◽  
Cardiometabolic Traits

Identification of genetic risk factors that are shared between Alzheimer's disease (AD) and other traits, i.e., pleiotropy, can help improve our understanding of the etiology of AD and potentially detect new therapeutic targets. Motivated by previous epidemiological correlations observed between cardiometabolic traits and AD, we performed a set of bivariate genome-wide association studies coupled with colocalization analysis to identify loci that are shared between AD and eleven cardiometabolic traits. We identified three previously unreported pleiotropic trait associations at known AD loci as well as four novel pleiotropic loci. One associated locus was tagged by a low-frequency coding variant in the gene DOCK4 and is potentially implicated in its alternative splicing. Statistical colocalization with expression quantitative trait loci identified by the Genotype-Tissue Expression (GTEx) project identified additional candidate genes, including ACE, the target of the hypertensive drug class of ACE-inhibitors. We found that the allele associated with decreased ACE expression in brain tissue was also associated with increased risk of AD, providing human genetic evidence of a potential increase in AD risk from use of an established anti-hypertensive therapeutic. Overall, our results support a complex genetic relationship between AD and these cardiometabolic traits, and the candidate causal genes identified suggest that blood pressure and immune response play a role in the pleiotropy between these traits.

scholarly journals Causal effect of Insulin Resistance on Small Vessel Stroke and Alzheimer's Disease: A Mendelian Randomization Analysis

2021 ◽  
Author(s):  
Mengyuan Zhou ◽  
Hao Li ◽  
Yongjun Wang ◽  
Yuesong Pan ◽  
Yilong Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Gold Standard ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Small Vessel ◽  
European Ancestry ◽  
Fasting Insulin ◽  
Inverse Variance

Abstract Background The causal effect of insulin resistance on small vessel stroke and Alzheimer Disease was controversial in previous studies. Methods We selected 12 single-nucleotide polymorphisms (SNPs) associated with body mass index (BMI)-adjusted fasting insulin levels and 5 SNPs associated with gold standard measures of insulin resistance as instrumental variables in Mendelian randomization (MR) analyses. Summary statistical data of SNP-small vessel stroke and of SNP-AD associations were derived from the Multi-ancestry Genome-Wide Association Study of Stroke Consortium and Psychiatric Genomics Consortium-Alzheimer’s Disease Workgroup data of individuals of European ancestry. Two-sample MR estimates were conducted with inverse-variance-weighted, robust inverse-variance-weighted, simple median, weighted median, weighted mode-based estimator, and MR pleiotropy residual sum and outlier methods. Results Genetically predicted higher insulin resistance had a higher odds ratio (OR) of small vessel stroke (OR 1.23; 95% confidence interval [CI] 1.05–1.44; P = 0.01 using BMI-adjusted fasting insulin; OR 1.25; 95% CI 1.07–1.46; P = 0.006 using gold standard measure of insulin resistance) and AD (OR 1.13; 95% CI 1.04–1.23; P = 0.004 using BMI-adjusted fasting insulin; OR 1.02; 95% CI 1.00-1.03; P = 0.03 using gold standard measures of insulin resistance) using the inverse-variance-weighted method. No evidence of pleiotropy was found using MR-Egger regression. Conclusion Our findings provide genetic support for a causal effect of insulin resistance on small vessel stroke and AD. Further investigation on the involved mechanisms is needed.

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

2020 ◽  
Vol 49 (4) ◽  
pp. 1163-1172 ◽  
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 ◽  
Bidirectional Relationship ◽  
Robust Evidence ◽  
Years Of Schooling

Abstract Objectives To examine whether educational attainment and intelligence have causal effects on risk of Alzheimer’s disease (AD), independently of each other. Design Two-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 AD risk. Participants 17 008 AD cases and 37 154 controls from the International Genomics of Alzheimer’s Project (IGAP) consortium. Main outcome measure Odds ratio (OR) of AD per standardized deviation increase in years of schooling (SD = 3.6 years) and intelligence (SD = 15 points on intelligence test). Results There was strong evidence of a causal, bidirectional relationship between intelligence and educational attainment, with the magnitude of effect being similar in both directions [OR for intelligence on education = 0.51 SD units, 95% confidence interval (CI): 0.49, 0.54; OR for education on intelligence = 0.57 SD units, 95% CI: 0.48, 0.66]. 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: 23–49%) and 35% (95% CI: 25–43%) lower, respectively. There was little evidence from the multivariable MR analysis that educational attainment affected AD risk once intelligence was taken into account (OR = 1.15, 95% CI: 0.68–1.93), but intelligence affected AD risk independently of educational attainment to a similar magnitude observed in the univariate analysis (OR = 0.69, 95% CI: 0.44–0.88). Conclusions There is robust evidence for an independent, causal effect of intelligence in lowering AD risk. The causal effect of educational attainment on AD risk is likely to be mediated by intelligence.

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