Definition of Late Onset Alzheimer’s Disease and Anticipation Effect of Genome-Wide Significant Risk Variants: Pilot Study of the APOE e4 Allele

2018 ◽  
Vol 77 (1) ◽  
pp. 8-12 ◽  
Author(s):  
Vincenzo De Luca ◽  
Gianfranco Spalletta ◽  
Renan P. Souza ◽  
Ariel Graff ◽  
Luciana Bastos-Rodrigues ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pilot Study ◽  
Late Onset ◽  
Significant Risk ◽  
Risk Variants ◽  
Genome Wide ◽  
E4 Allele ◽  
Definition Of ◽  
Anticipation Effect

scholarly journals Genetically regulated expression in late-onset Alzheimer’s disease implicates risk genes within known and novel loci

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hung-Hsin Chen ◽  
Lauren E. Petty ◽  
Jin Sha ◽  
Yi Zhao ◽  
Amanda Kuzma ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Meta Analysis ◽  
Data Sets ◽  
Phenotypic Variance ◽  
Risk Variants ◽  
Genome Wide ◽  
Regulated Expression ◽  
Genetic Mechanisms

AbstractLate-onset Alzheimer disease (LOAD) is highly polygenic, with a heritability estimated between 40 and 80%, yet risk variants identified in genome-wide studies explain only ~8% of phenotypic variance. Due to its increased power and interpretability, genetically regulated expression (GReX) analysis is an emerging approach to investigate the genetic mechanisms of complex diseases. Here, we conducted GReX analysis within and across 51 tissues on 39 LOAD GWAS data sets comprising 58,713 cases and controls from the Alzheimer’s Disease Genetics Consortium (ADGC) and the International Genomics of Alzheimer’s Project (IGAP). Meta-analysis across studies identified 216 unique significant genes, including 72 with no previously reported LOAD GWAS associations. Cross-brain-tissue and cross-GTEx models revealed eight additional genes significantly associated with LOAD. Conditional analysis of previously reported loci using established LOAD-risk variants identified eight genes reaching genome-wide significance independent of known signals. Moreover, the proportion of SNP-based heritability is highly enriched in genes identified by GReX analysis. In summary, GReX-based meta-analysis in LOAD identifies 216 genes (including 72 novel genes), illuminating the role of gene regulatory models in LOAD.

scholarly journals Genetic data and cognitively-defined late-onset Alzheimer’s disease subgroups

2018 ◽  
Author(s):  
Shubhabrata Mukherjee ◽  
Jesse Mez ◽  
Emily Trittschuh ◽  
Andrew J. Saykin ◽  
Laura E. Gibbons ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Disease Diagnosis ◽  
Single Nucleotide ◽  
Total N ◽  
Snp Data ◽  
Genotype Frequencies ◽  
Genome Wide ◽  
E4 Allele

AbstractCategorizing people with late-onset Alzheimer’s disease into biologically coherent subgroups is important for personalized medicine. We evaluated data from five studies (total n=4 050, of whom 2 431 had genome-wide single nucleotide polymorphism (SNP) data). We assigned people to cognitively-defined subgroups on the basis of relative performance in memory, executive functioning, visuospatial functioning, and language at the time of Alzheimer’s disease diagnosis. We compared genotype frequencies for each subgroup to those from cognitively normal elderly controls. We focused on APOE and on SNPs with p<10-5 and odds ratios more extreme than those previously reported for Alzheimer’s disease (<0.77 or >1.30). There was substantial variation across studies in the proportions of people in each subgroup. In each study, higher proportions of people with isolated substantial relative memory impairment had ≥1 APOE e4 allele than any other subgroup (overall p= 1.5 × 10-27). Across subgroups, there were 33 novel suggestive loci across the genome with p<10-5 and an extreme OR compared to controls, of which none had statistical evidence of heterogeneity and 30 had ORs in the same direction across all datasets. These data support the biological coherence of cognitively-defined subgroups and nominate novel genetic loci.

scholarly journals Prediction of Alzheimer's disease using multi-variants from a Chinese genome-wide association study

Brain ◽  
2020 ◽  
Author(s):  
Longfei Jia ◽  
Fangyu Li ◽  
Cuibai Wei ◽  
Min Zhu ◽  
Qiumin Qu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Study ◽  
Predictive Models ◽  
Genome Wide Association Study ◽  
Disease Onset ◽  
Genome Wide Association ◽  
Nucleotide Polymorphisms ◽  
Risk Variants ◽  
Genome Wide

Abstract Previous genome-wide association studies have identified dozens of susceptibility loci for sporadic Alzheimer’s disease, but few of these loci have been validated in longitudinal cohorts. Establishing predictive models of Alzheimer’s disease based on these novel variants is clinically important for verifying whether they have pathological functions and provide a useful tool for screening of disease risk. In the current study, we performed a two-stage genome-wide association study of 3913 patients with Alzheimer’s disease and 7593 controls and identified four novel variants (rs3777215, rs6859823, rs234434, and rs2255835; Pcombined = 3.07 × 10−19, 2.49 × 10−23, 1.35 × 10−67, and 4.81 × 10−9, respectively) as well as nine variants in the apolipoprotein E region with genome-wide significance (P &lt; 5.0 × 10−8). Literature mining suggested that these novel single nucleotide polymorphisms are related to amyloid precursor protein transport and metabolism, antioxidation, and neurogenesis. Based on their possible roles in the development of Alzheimer’s disease, we used different combinations of these variants and the apolipoprotein E status and successively built 11 predictive models. The predictive models include relatively few single nucleotide polymorphisms useful for clinical practice, in which the maximum number was 13 and the minimum was only four. These predictive models were all significant and their peak of area under the curve reached 0.73 both in the first and second stages. Finally, these models were validated using a separate longitudinal cohort of 5474 individuals. The results showed that individuals carrying risk variants included in the models had a shorter latency and higher incidence of Alzheimer’s disease, suggesting that our models can predict Alzheimer’s disease onset in a population with genetic susceptibility. The effectiveness of the models for predicting Alzheimer’s disease onset confirmed the contributions of these identified variants to disease pathogenesis. In conclusion, this is the first study to validate genome-wide association study-based predictive models for evaluating the risk of Alzheimer’s disease onset in a large Chinese population. The clinical application of these models will be beneficial for individuals harbouring these risk variants, and particularly for young individuals seeking genetic consultation.

scholarly journals Genome-wide significant, replicated and functional risk variants for Alzheimer’s disease

2017 ◽  
Vol 124 (11) ◽  
pp. 1455-1471 ◽  
Author(s):  
Xiaoyun Guo ◽  
Wenying Qiu ◽  
Rolando Garcia-Milian ◽  
Xiandong Lin ◽  
Yong Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Variants ◽  
Genome Wide

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 Late Onset Alzheimer’s Disease Risk Variants in Cognitive Decline: The PATH Through Life Study

2017 ◽  
Vol 57 (2) ◽  
pp. 423-436 ◽  
Author(s):  
Shea J. Andrews ◽  
Debjani Das ◽  
Kaarin J. Anstey ◽  
Simon Easteal
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Disease Risk ◽  
Late Onset ◽  
Life Study ◽  
Risk Variants
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