Integrated approaches in next-generation sequence data analysis for dissecting the molecular mechanisms in late-onset Alzheimer’s disease

2019 ◽  
Author(s):  
John Stephen Malamon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Data Analysis ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Sequence Data ◽  
Next Generation ◽  
Integrated Approaches

scholarly journals PRECISION MEDICINE - THE GOLDEN GATE FOR DETECTION, TREATMENT AND PREVENTION OF ALZHEIMER’S DISEASE

2016 ◽  
pp. 1-17
Author(s):  
H. Hampel ◽  
S.E. O’Bryant ◽  
J.I. Castrillo ◽  
C. Ritchie ◽  
K. Rojkova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Precision Medicine ◽  
Molecular Mechanisms ◽  
Clinical Symptoms ◽  
Late Onset ◽  
Therapeutic Success ◽  
Preclinical Stage ◽  
Treatment And Prevention

During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer’s disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi-factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical “one-size-fits-all” approach in drug discovery towards biomarker guided “molecularly” tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic.

scholarly journals Genome-Wide Meta-Analysis of Late-Onset Alzheimer's Disease Using Rare Variant Imputation in 324,809 Subjects Identifies Novel Rare Variant Locus NCK2: The International Genomics of Alzheimer's Project (IGAP)

2021 ◽  
Author(s):  
Adam C. Naj ◽  
Ganna Leonenko ◽  
Xueqiu Jian ◽  
Benjamin Grenier-Boley ◽  
Maria Carolina Dalmasso ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rare Variant ◽  
Late Onset ◽  
Sequence Data ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
The Uk

Risk for late-onset Alzheimer's disease (LOAD) is driven by multiple loci primarily identified by genome-wide association studies, many of which are common variants with minor allele frequencies (MAF)>0.01. To identify additional common and rare LOAD risk variants, we performed a GWAS on 25,170 LOAD subjects and 41,052 cognitively normal controls in 44 datasets from the International Genomics of Alzheimer's Project (IGAP). Existing genotype data were imputed using the dense, high-resolution Haplotype Reference Consortium (HRC) r1.1 reference panel. Stage 1 associations of P<10-5 were meta-analyzed with the European Alzheimer's Disease Biobank (EADB) (n=20,301 cases; 21,839 controls) (stage 2 combined IGAP and EADB). An expanded meta-analysis was performed using a GWAS of parental AD/dementia history in the UK Biobank (UKBB) (n=35,214 cases; 180,791 controls) (stage 3 combined IGAP, EADB, and UKBB). Common variant (MAF≥0.01) associations were identified for 29 loci in stage 2, including novel genome-wide significant associations at TSPAN14 (P=2.33×10-12), SHARPIN (P=1.56×10-9), and ATF5/SIGLEC11 (P=1.03[mult]10-8), and newly significant associations without using AD proxy cases in MTSS1L/IL34 (P=1.80×10-8), APH1B (P=2.10×10-13), and CLNK (P=2.24×10-10). Rare variant (MAF<0.01) associations with genome-wide significance in stage 2 included multiple variants in APOE and TREM2, and a novel association of a rare variant (rs143080277; MAF=0.0054; P=2.69×10-9) in NCK2, further strengthened with the inclusion of UKBB data in stage 3 (P=7.17×10-13). Single-nucleus sequence data shows that NCK2 is highly expressed in amyloid-responsive microglial cells, suggesting a role in LOAD pathology.

scholarly journals Early-Onset Alzheimer’s Disease: What Is Missing in Research?

2021 ◽  
Vol 21 (2) ◽  
Author(s):  
Temitope Ayodele ◽  
Ekaterina Rogaeva ◽  
Jiji T. Kurup ◽  
Gary Beecham ◽  
Christiane Reitz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Molecular Mechanisms ◽  
Rare Variants ◽  
Late Onset ◽  
Aggressive Disease ◽  
Clinical Biomarker ◽  
Early Onset Alzheimer’S Disease ◽  
Made In

Abstract Purpose of Review Early-onset Alzheimer’s disease (EOAD), defined as Alzheimer’s disease (AD) occurring before age 65, is significantly less well studied than the late-onset form (LOAD) despite EOAD often presenting with a more aggressive disease progression. The aim of this review is to summarize the current understanding of the etiology of EOAD, their translation into clinical practice, and to suggest steps to be taken to move our understanding forward. Recent Findings EOAD cases make up 5–10% of AD cases but only 10–15% of these cases show known mutations in the APP, PSEN1, and PSEN2, which are linked to EOAD. New data suggests that these unexplained cases following a non-Mendelian pattern of inheritance is potentially caused by a mix of common and newly discovered rare variants. However, only a fraction of this genetic variation has been identified to date leaving the molecular mechanisms underlying this type of AD and their association with clinical, biomarker, and neuropathological changes unclear. Summary While great advancements have been made in characterizing EOAD, much work is needed to disentangle the molecular mechanisms underlying this type of AD and to identify putative targets for more precise disease screening, diagnosis, prevention, and treatment.

scholarly journals Inferring the molecular mechanisms of noncoding Alzheimer’s disease-associated genetic variants

2018 ◽  
Author(s):  
Alexandre Amlie-Wolf ◽  
Mitchell Tang ◽  
Jessica Way ◽  
Beth Dombroski ◽  
Ming Jiang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Genome Wide Association Study ◽  
Late Onset ◽  
Regulatory Mechanisms ◽  
Luciferase Expression ◽  
Tissue Specific ◽  
Causal Variants

Structured AbstractINTRODUCTIONWe set out to characterize the causal variants, regulatory mechanisms, tissue contexts, and target genes underlying noncoding late-onset Alzheimer’s Disease (LOAD)-associated genetic signals.METHODSWe applied our INFERNO method to the IGAP genome-wide association study (GWAS) data, annotating all potentially causal variants with tissue-specific regulatory activity. Bayesian co-localization analysis of GWAS summary statistics and eQTL data was performed to identify tissue-specific target genes.RESULTSINFERNO identified enhancer dysregulation in all 19 tag regions analyzed, significant enrichments of enhancer overlaps in the immune-related blood category, and co-localized eQTL signals overlapping enhancers from the matching tissue class in ten regions (ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, EPHA1, FERMT2, ZCWPW1). We validated the allele-specific effects of several variants on enhancer function using luciferase expression assays.DISCUSSIONIntegrating functional genomics with GWAS signals yielded insights into the regulatory mechanisms, tissue contexts, and genes affected by noncoding genetic variation associated with LOAD risk.

scholarly journals IPSC-derived neuronal cultures expressing the Alzheimer’s disease associated rare TREM2 R47H variant enables the construction of an Aβ-induced gene regulatory network

2019 ◽  
Author(s):  
Soraia Martins ◽  
Andreas Müller-Schiffmann ◽  
Martina Bohndorf ◽  
Wasco Wruck ◽  
Kristel Sleegers ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Response ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Neuronal Cultures ◽  
Gene Regulatory

AbstractRecently, genes associated with immune response and inflammation have been identified as genetic risk factors for late-onset Alzheimer’s disease (LOAD). One of them is the rare p.Arg47His (R47H) variant within triggering receptor expressed on myeloid cells 2 (TREM2), which has been shown to increase the risk for developing AD 2-3-fold. Here, we report the generation and characterization of a model of LOAD using lymphoblast-derived iPSCs from patients harbouring the R47H mutation in TREM2 (AD TREM2 iPSCs), as well as from control individuals without dementia (CON iPSCs). iPSCs efficiently differentiate into mature neuronal cultures and comparative global transcriptome analysis identified a distinct gene expression profile in AD TREM2 neuronal cultures. Furthermore, manipulation of the iPSC-derived functional neuronal cultures with an Aβ-S8C dimer highlighted metabolic pathways, phagosome and immune response as the most perturbed pathways in AD TREM2 neuronal cultures. Through the construction of an Aβ-induced gene regulatory network, we were able to identify an Aβ signature linked to protein processing in the endoplasmic reticulum (ER) which emphasised ER-stress, as a potential causal role in LOAD. Overall, this study has shown that our AD-iPSC based model can be used for in-depth studies to better understand the molecular mechanisms underlying the etiology of LOAD and provides new opportunities for screening of potential therapeutic targets.

scholarly journals IPSC-Derived Neuronal Cultures Carrying the Alzheimer’s Disease Associated TREM2 R47H Variant Enables the Construction of an Aβ-Induced Gene Regulatory Network

2020 ◽  
Vol 21 (12) ◽  
pp. 4516
Author(s):  
Soraia Martins ◽  
Andreas Müller-Schiffmann ◽  
Lars Erichsen ◽  
Martina Bohndorf ◽  
Wasco Wruck ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Response ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Neuronal Cultures ◽  
Gene Regulatory ◽  
Induced Pluripotent

Genes associated with immune response and inflammation have been identified as genetic risk factors for late-onset Alzheimer´s disease (LOAD). The rare R47H variant within triggering receptor expressed on myeloid cells 2 (TREM2) has been shown to increase the risk for developing Alzheimer’s disease (AD) 2–3-fold. Here, we report the generation and characterization of a model of late-onset Alzheimer’s disease (LOAD) using lymphoblast-derived induced pluripotent stem cells (iPSCs) from patients carrying the TREM2 R47H mutation, as well as from control individuals without dementia. All iPSCs efficiently differentiated into mature neuronal cultures, however AD neuronal cultures showed a distinct gene expression profile. Furthermore, manipulation of the iPSC-derived neuronal cultures with an Aβ-S8C dimer highlighted metabolic pathways, phagosome and immune response as the most perturbed pathways in AD neuronal cultures. Through the construction of an Aβ-induced gene regulatory network, we were able to identify an Aβ signature linked to protein processing in the endoplasmic reticulum (ER), which emphasized ER-stress, as a potential causal role in LOAD. Overall, this study has shown that our AD-iPSC based model can be used for in-depth studies to better understand the molecular mechanisms underlying the etiology of LOAD and provides new opportunities for screening of potential therapeutic targets.

scholarly journals ABCA7—A Member of the ABC Transporter Family in Healthy and Ailing Brain

2020 ◽  
Vol 10 (2) ◽  
pp. 121
Author(s):  
Alexei A. Surguchev ◽  
Andrei Surguchov
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Transporter Family ◽  
New Findings ◽  
A Cell ◽  
Underlying Mechanisms ◽  
Meta Analyses

Identification of genetic markers of a human disease, which is generally sporadic, may become an essential tool for the investigation of its molecular mechanisms. The role of ABCA7 in Alzheimer’s disease (AD) was discovered less than ten years ago when meta-analyses provided evidence that rs3764650 is a new AD susceptibility locus. Recent research advances in this locus and new evidence regarding ABCA7 contribution to the AD pathogenesis brought a new understanding of the underlying mechanisms of this disorder. An interesting, up-to-date review article "ABCA7 and Pathogenic Pathways of Alzheimer’s Disease" by Aikawa et al. (2018), outlines the ABCA7 role in AD and summarizes new findings in this exciting area. ABC transporters or ATP-binding cassette transporters are a superfamily of proteins belonging to a cell transport system. Currently, members of the family are the focus of attention because of their central role in drug pharmacokinetics. Two recent findings are the reason why much attention is drawn to the ABCA7 family. First, is the biochemical data showing a role of ABCA7 in amyloid pathology. Second, genetic data identifying ABCA7 gene variants as loci responsible for the late-onset AD. These results point to the ABCA7 as a significant new contributor to the pathogenesis of AD.

scholarly journals Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

2019 ◽  
Author(s):  
Minghui Wang ◽  
Aiqun Li ◽  
Michiko Sekiya ◽  
Noam D. Beckmann ◽  
Xiuming Quan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Brain Regions ◽  
Molecular Networks ◽  
Parahippocampal Gyrus ◽  
Specific Gene ◽  
Neuronal System ◽  
Full Spectrum

SUMMARYTo study the molecular mechanisms driving the pathogenesis and identify novel therapeutic targets of late onset Alzheimer’s Disease (LOAD), we performed an integrative network analysis of whole-genome DNA and RNA sequencing profiling of four cortical areas, including the parahippocampal gyrus, across 364 donors spanning the full spectrum of LOAD-related cognitive and neuropathological disease severities. Our analyses revealed thousands of molecular changes and uncovered for the first-time multiple neuron specific gene subnetworks most dysregulated in LOAD. ATP6V1A, a critical subunit of vacuolar-type H+-ATPase (v-ATPase), was predicted to be a key regulator of one neuronal subnetwork and its role in disease-related processes was evaluated through CRISPR-based manipulation of human induced pluripotent stem cell derived neurons and RNAi-based knockdown in transgenic Drosophila models. This study advances our understanding of LOAD pathogenesis by providing the global landscape and detailed circuits of complex molecular interactions and regulations in several key brain regions affected by LOAD and the resulting network models provide a blueprint for developing next generation therapeutics against LOAD.

Recent studies on cellular and molecular mechanisms in Alzheimer’s disease: focus on epigenetic factors and histone deacetylase

2018 ◽  
Vol 29 (3) ◽  
pp. 241-260 ◽  
Author(s):  
Harikesh Dubey ◽  
Kavita Gulati ◽  
Arunabha Ray
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Association Studies ◽  
Hdac Inhibitors ◽  
Epigenetic Modifications ◽  
Genome Wide Association Studies ◽  
Risk Genes ◽  
Genome Wide

AbstractAlzheimer’s disease (AD) is one of the most common neurodegenerative disorders mainly affecting elderly people. It is characterized by progressive loss of memory and cognitive function. More than 95% of AD cases are related to sporadic or late-onset AD (LOAD). The etiology of LOAD is still unclear. It has been reported that environmental factors and epigenetic alterations play a significant role in AD pathogenesis. Furthermore, recently, genome-wide association studies (GWAS) identified 10 novel risk genes:ABCA7,APOE,BIN1,CD2AP,CD33,CLU,CR1,MS4A6A,MS4A4E, andPICALM, which play an important role for LOAD. In this review, the therapeutic approaches of AD by epigenetic modifications have been discussed. Nowadays, HDAC inhibitors have clinically proven its activity for epigenetic modifications. Furthermore, we try to establish the relationship between HDAC inhibitors and above mentioned LOAD risk genes. Finally, we are hoping that this review may open new area of research for AD treatment.

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