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 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 Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

2018 ◽  
Author(s):  
BW Kunkle ◽  
B Grenier-Boley ◽  
R Sims ◽  
JC Bis ◽  
AC Naj ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rare Variants ◽  
Late Onset ◽  
Association Studies ◽  
Meta Analysis ◽  
The Elderly ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Load Risk

IntroductionLate-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS)3–8. To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7) indicating that additional rare variants remain to be identified.

scholarly journals A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jun Young Park ◽  
Dongsoo Lee ◽  
Jang Jae Lee ◽  
Jungsoo Gim ◽  
Tamil Iniyan Gunasekaran ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Thickness ◽  
Association Studies ◽  
Brain Magnetic Resonance Imaging ◽  
Amyloid Β ◽  
Missense Variant ◽  
Hippocampal Volume ◽  
Genome Wide Association Studies ◽  
Increased Risk

AbstractEstablished genetic risk factors for Alzheimer’s disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10−9) and hippocampal volume (p = 5.1 × 10−12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-β accumulation (p = 0.03) and measures of memory (p = 1.0 × 10−4) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer’s Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10−6) and AddNeuroMed (rs138412600, p = 5.9 × 10−5) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.

scholarly journals ABCA7 and Pathogenic Pathways of Alzheimer’s Disease

2018 ◽  
Vol 8 (2) ◽  
pp. 27 ◽  
Author(s):  
◽  
◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Amyloid Β ◽  
Current Evidence ◽  
Genome Wide Association Studies ◽  
In Vivo Models ◽  
Peripheral Tissues ◽  
Increased Risk ◽  
The Brain

The ATP-binding cassette (ABC) reporter family functions to regulate the homeostasis of phospholipids and cholesterol in the central nervous system, as well as peripheral tissues. ABCA7 belongs to the A subfamily of ABC transporters, which shares 54% sequence identity with ABCA1. While ABCA7 is expressed in a variety of tissues/organs, including the brain, recent genome-wide association studies (GWAS) have identified ABCA7 gene variants as susceptibility loci for late-onset Alzheimer’s disease (AD). More important, subsequent genome sequencing analyses have revealed that premature termination codon mutations in ABCA7 are associated with the increased risk for AD. Alzheimer’s disease is a progressive neurodegenerative disease and the most common cause of dementia, where the accumulation and deposition of amyloid-β (Aβ) peptides cleaved from amyloid precursor protein (APP) in the brain trigger the pathogenic cascade of the disease. In consistence with human genetic studies, increasing evidence has demonstrated that ABCA7 deficiency exacerbates Aβ pathology using in vitro and in vivo models. While ABCA7 has been shown to mediate phagocytic activity in macrophages, ABCA7 is also involved in the microglial Aβ clearance pathway. Furthermore, ABCA7 deficiency results in accelerated Aβ production, likely by facilitating endocytosis and/or processing of APP. Taken together, current evidence suggests that ABCA7 loss-of-function contributes to AD-related phenotypes through multiple pathways. A better understanding of the function of ABCA7 beyond lipid metabolism in both physiological and pathological conditions becomes increasingly important to explore AD pathogenesis.

Genetically Predicted Coffee Consumption and Risk of Alzheimer’s Disease and Stroke

2021 ◽  
Vol 83 (4) ◽  
pp. 1815-1823
Author(s):  
Zhizhong Zhang ◽  
Mengmeng Wang ◽  
Shuai Yuan ◽  
Huan Cai ◽  
Shuang-Gen Zhu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stroke Risk ◽  
Association Studies ◽  
Coffee Consumption ◽  
Genome Wide Association Studies ◽  
Biological Mechanisms ◽  
Genome Wide ◽  
Level Data ◽  
Increased Risk

Background: Observational studies have reported that coffee consumption was associated with Alzheimer’s disease (AD) and stroke risk. However, the results are inconclusive. Objective: We aimed to evaluate whether genetically predicted coffee consumption is associated with AD and stroke using Mendelian randomization (MR) design. Methods: Summary-level data for AD (n = 54,162), ischemic stroke (n = 440,328), and intracerebral hemorrhage (ICH, n = 3,026) were adopted from publicly available databases. Summary-level data for coffee consumption were obtained from two genome-wide association studies, comprising up to 375,833 subjects. Results: Genetically predicted coffee consumption (cups/day) was associated with an increased risk of AD (OR = 1.26, 95%CI = 1.05–1.51). Moreover, genetically predicted 50%increase of coffee consumption was associated with an increased risk of ICH (OR: 2.27, 95%CI: 1.08–4.78) but a decreased risk of small vessel stroke (OR: 0.71, 95%CI: 0.51–0.996). Estimate for AD and ICH in FinnGen consortium is directionally consistent. Combined analysis of different databases further confirmed that genetically predicted coffee consumption was associated with an increased risk of AD and ICH. In the multivariable MR analysis, genetically predicted coffee consumption retained a stable effect with AD and ICH when adjusting for smoking (p < 0.05), while the association with AD attenuated when adjusting for alcohol use. Conclusion: Our results indicate that genetically predicted coffee consumption may be associated with an increased risk of AD and ICH. The underlying biological mechanisms warrant further study.

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

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
William P. Bone ◽  
◽  
Katherine M. Siewert ◽  
Anupama Jha ◽  
Derek Klarin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Low Frequency ◽  
Tissue Expression ◽  
Genome Wide Association Studies ◽  
Frequency Coding ◽  
Increased Risk ◽  
Causal Genes ◽  
Cardiometabolic Traits

Abstract Background 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. Previous epidemiological correlations observed between cardiometabolic traits and AD led us to assess the pleiotropy between these traits. Methods 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. For each of these loci, we performed colocalization with Genotype-Tissue Expression (GTEx) project expression quantitative trait loci (eQTL) to identify candidate causal genes. Results 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. Colocalization with GTEx eQTL data identified additional candidate genes for the loci we detected, 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. Conclusion 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 Exome-wide age-of-onset analysis reveals exonic variants in ERN1 and SPPL2C associated with Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Liang He ◽  
◽  
Yury Loika ◽  
Yongjin Park ◽  
David A. Bennett ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Age Of Onset ◽  
Association Studies ◽  
Missense Variant ◽  
Brain Regions ◽  
Posterior Cingulate Cortex ◽  
Minor Allele ◽  
Eqtl Analysis ◽  
Genome Wide Association Studies

AbstractDespite recent discoveries in genome-wide association studies (GWAS) of genomic variants associated with Alzheimer’s disease (AD), its underlying biological mechanisms are still elusive. The discovery of novel AD-associated genetic variants, particularly in coding regions and from APOEε4 non-carriers, is critical for understanding the pathology of AD. In this study, we carried out an exome-wide association analysis of age-of-onset of AD with ~20,000 subjects and placed more emphasis on APOEε4 non-carriers. Using Cox mixed-effects models, we find that age-of-onset shows a stronger genetic signal than AD case-control status, capturing many known variants with stronger significance, and also revealing new variants. We identified two novel variants, rs56201815, a rare synonymous variant in ERN1, and rs12373123, a common missense variant in SPPL2C in the MAPT region in APOEε4 non-carriers. Besides, a rare missense variant rs144292455 in TACR3 showed the consistent direction of effect sizes across all studies with a suggestive significant level. In an attempt to unravel their regulatory and biological functions, we found that the minor allele of rs56201815 was associated with lower average FDG uptake across five brain regions in ADNI. Our eQTL analyses based on 6198 gene expression samples from ROSMAP and GTEx revealed that the minor allele of rs56201815 was potentially associated with elevated expression of ERN1, a key gene triggering unfolded protein response (UPR), in multiple brain regions, including the posterior cingulate cortex and nucleus accumbens. Our cell-type-specific eQTL analysis using ~80,000 single nuclei in the prefrontal cortex revealed that the protective minor allele of rs12373123 significantly increased the expression of GRN in microglia, and was associated with MAPT expression in astrocytes. These findings provide novel evidence supporting the hypothesis of the potential involvement of the UPR to ER stress in the pathological pathway of AD, and also give more insights into underlying regulatory mechanisms behind the pleiotropic effects of rs12373123 in multiple degenerative diseases including AD and Parkinson’s disease.

scholarly journals CD33 in Alzheimer’s Disease – Biology, Pathogenesis, and Therapeutics: A Mini-Review

Gerontology ◽  
2018 ◽  
Vol 65 (4) ◽  
pp. 323-331 ◽  
Author(s):  
Lingzhi Zhao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Disease Biology ◽  
Increased Risk ◽  
Disease Modifying ◽  
Ad Prevention ◽  
Disease Modifying Treatment

Alzheimer’s disease (AD) affects nearly 50 million people worldwide, and currently no disease-modifying treatment is available. With continuous failure of anti-amyloid-beta- or tau-based therapies, identification of new targets has become an urgent necessity for AD prevention and therapy. Recently, conventional genetic approaches and computational strategies have converged on immune-inflammatory pathways as key events in the pathogenesis of AD. A number of genes have been highly linked to the onset and development of late-onset sporadic AD, the most common form of AD. Strikingly, most of these genes are involved in microglial biology. Mutations and/or differential expression of microglial receptors such as TREM2, CD33, and CR3 have been strongly associated with an increased risk of developing AD. The mechanistic actions of these risk factors in AD etiology have been actively investigated since they were identified. Whether these genes can be targeted for a disease-modifying treatment is under hot debate. CD33 is one of the top-ranked AD risk genes identified by genome-wide association studies. This review summarizes the recently advanced biology of CD33 and its association with AD. It also provides insights from a drug discovery perspective into the druggability, therapeutic strategies, and challenges to target CD33 for treating this devastating disorder.

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

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.

Sign in / Sign up

Export Citation Format

Share Document