scholarly journals Genes, pathways and risk prediction in Alzheimer’s disease

2019 ◽  
Author(s):  
John Hardy ◽  
Valentina Escott-Price
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Membrane Damage ◽  
Disease Process ◽  
Complete Understanding ◽  
Induced Membrane ◽  
Genome Wide ◽  
Key Factor ◽  
Risk Of Disease

Abstract The failure of recent clinical trials in Alzheimer's disease has highlighted the need for the development of a more complete understanding of the pathogenesis of the disorder and also a belief that therapies may only work if given very early in the disease process before overt symptoms occur. The rare, early onset forms of the disease are all caused by mutations which make amyloid deposition a more likely event. Here we discuss the recent data showing that, in contrast, much of the risk of late onset disease is encoded by loci involved in lipid metabolism and/or encoded by microglia. We discuss these finding and suggest that amyloid induced membrane damage may be a key factor in disease and also review the evidence that genome wide genetic analysis can substantially help in the prediction of those individuals at high risk of disease in the general population.

scholarly journals Association Study of Genetic Variants inCDKN2A/CDKN2BGenes/Loci with Late-Onset Alzheimer's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-4
Author(s):  
Andrea Tedde ◽  
Irene Piaceri ◽  
Silvia Bagnoli ◽  
Ersilia Lucenteforte ◽  
Uwe Ueberham ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Genetic Variant ◽  
Case Control Study ◽  
Late Onset ◽  
Common Genetic Variant ◽  
Genome Wide ◽  
Control Study

Alzheimer's disease (AD) is the most common form of dementia clinically characterized by progressive impairment of memory and other cognitive functions. Many genetic researches in AD identified one common genetic variant (ε4) in Apolipoprotein E (APOE) gene as a risk factor for the disease. Two independent genome-wide studies demonstrated a new locus on chromosome 9p21.3 implicated in Late-Onset Alzheimer's Disease (LOAD) susceptibility in Caucasians. In the present study, we investigated the role of three SNP's in theCDKN2Agene (rs15515, rs3731246, and rs3731211) and one in theCDKN2Bgene (rs598664) located in 9p21.3 using an association case-control study carried out in a group of Caucasian subjects including 238 LOAD cases and 250 controls. The role ofCDKN2AandCDKN2Bgenetic variants in AD is not confirmed in our LOAD patients, and further studies are needed to elucidate the role of these genes in the susceptibility of AD.

scholarly journals Genetic underpinnings in Alzheimer’s disease – a review

2017 ◽  
Vol 29 (1) ◽  
pp. 21-38 ◽  
Author(s):  
Ahmed A. Moustafa ◽  
Mubashir Hassan ◽  
Doaa H. Hewedi ◽  
Iman Hewedi ◽  
Julia K. Garami ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Genetic Research ◽  
Twin Studies ◽  
Pedigree Analysis ◽  
Protein Signaling ◽  
Genetic Components ◽  
Genome Wide ◽  
Pharmacological Targets

AbstractIn this review, we discuss the genetic etiologies of Alzheimer’s disease (AD). Furthermore, we review genetic links to protein signaling pathways as novel pharmacological targets to treat AD. Moreover, we also discuss the clumps of AD-m ediated genes according to their single nucleotide polymorphism mutations. Rigorous data mining approaches justified the significant role of genes in AD prevalence. Pedigree analysis and twin studies suggest that genetic components are part of the etiology, rather than only being risk factors for AD. The first autosomal dominant mutation in the amyloid precursor protein (APP) gene was described in 1991. Later, AD was also associated with mutated early-onset (presenilin 1/2,PSEN1/2andAPP) and late-onset (apolipoprotein E,ApoE) genes. Genome-wide association and linkage analysis studies with identified multiple genomic areas have implications for the treatment of AD. We conclude this review with future directions and clinical implications of genetic research in AD.

scholarly journals The Triggering Receptor Expressed on Myeloid Cells 2: “TREM-ming” the Inflammatory Component Associated with Alzheimer's Disease

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Troy T. Rohn
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Senile Plaques ◽  
Myeloid Cells ◽  
Disease Process ◽  
Age Related

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by a progressive loss of memory and cognitive skills. Although much attention has been devoted concerning the contribution of the microscopic lesions, senile plaques, and neurofibrillary tangles to the disease process, inflammation has long been suspected to play a major role in the etiology of AD. Recently, a novel variant in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has been identified that has refocused the spotlight back onto inflammation as a major contributing factor in AD. Variants in TREM2 triple one's risk of developing late-onset AD. TREM2 is expressed on microglial cells, the resident macrophages in the CNS, and functions to stimulate phagocytosis on one hand and to suppress cytokine production and inflammation on the other hand. The purpose of this paper is to discuss these recent developments including the potential role that TREM2 normally plays and how loss of function may contribute to AD pathogenesis by enhancing oxidative stress and inflammation within the CNS. In this context, an overview of the pathways linking beta-amyloid, neurofibrillary tangles (NFTs), oxidative stress, and inflammation will be discussed.

Alzheimer's disease genetics: lessons to improve disease modelling

2011 ◽  
Vol 39 (4) ◽  
pp. 910-916 ◽  
Author(s):  
Rita J. Guerreiro ◽  
John Hardy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Current Knowledge ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Biological Processes ◽  
Complete Understanding ◽  
Genome Wide ◽  
History Of ◽  
Ad Alzheimer’S Disease

In the present review, we look back at the recent history of GWAS (genome-wide association studies) in AD (Alzheimer's disease) and integrate the major findings with current knowledge of biological processes and pathways. These topics are essential for the development of animal models, which will be fundamental to our complete understanding of AD.

scholarly journals Predicting late-onset Alzheimer’s disease from genomic data using deep neural networks

2019 ◽  
Author(s):  
Javier de Velasco Oriol ◽  
Edgar E. Vallejo ◽  
Karol Estrada ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Neural Networks ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Deep Neural Networks ◽  
Late Onset ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Clinical Markers ◽  
Genome Wide

AbstractAlzheimer’s disease (AD) is the leading form of dementia. Over 25 million cases have been estimated worldwide and this number is predicted to increase two-fold every 20 years. Even though there is a variety of clinical markers available for the diagnosis of AD, the accurate and timely diagnosis of this disease remains elusive. Recently, over a dozen of genetic variants predisposing to the disease have been identified by genome-wide association studies. However, these genetic variants only explain a small fraction of the estimated genetic component of the disease. Therefore, useful predictions of AD from genetic data could not rely on these markers exclusively as they are not sufficiently informative predictors. In this study, we propose the use of deep neural networks for the prediction of late-onset Alzheimer’s disease from a large number of genetic variants. Experimental results indicate that the proposed model holds promise to produce useful predictions for clinical diagnosis of AD.

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 East Asian-specific novel loci associated with late-onset Alzheimer’s disease: the GARD cohort Genome-wide study

2020 ◽  
Author(s):  
Sarang Kang ◽  
Tamil Iniyan Gunasekaran ◽  
Kyu Yeong Choi ◽  
Jang Jae Lee ◽  
Sungho Won ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
Genetic Factors ◽  
Late Onset ◽  
East Asian ◽  
Genetic Heritability ◽  
Genome Wide ◽  
Japanese Sample ◽  
Genomic Studies

ABSTRACTThe high genetic heritability of Alzheimer’s disease has contributed to the multi-directional and large-scale genomic studies to discover genetic factors, and so far many massive studies have been reported. However, the majority of genetic factors have been identified through European races, and relatively few studies using East Asians to discover genetic factors. In this study, East Asian specific loci is first reported through GWAS using GARD cohorts, which have been intensively recruited and managed by a single institution. ApoE-stratified GWAS with the AD cases and matched controls (n=2,291) in the Korean cohort and validation analysis using a Japanese sample (n=1,956) replicated six previously reported loci (genes) including ApoE and suggested two novel susceptible loci in LRIG1 and CACNA1A gene. This study demonstrates that discovery of AD-associated variants can be accomplished in ethnic groups of a more homogeneous genetic background using samples comprising fewer subjects.

Sign in / Sign up

Export Citation Format

Share Document