scholarly journals Working Towards a Blood-Derived Gene Expression Biomarker Specific for Alzheimer’s Disease

2019 ◽  
Author(s):  
Hamel Patel ◽  
Raquel Iniesta ◽  
Daniel Stahl ◽  
Richard J.B Dobson ◽  
Stephen J Newhouse
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Classification Model ◽  
Ageing Population ◽  
Healthy Controls ◽  
Classification Models ◽  
Specific Expression ◽  
Expression Signature ◽  
Age Related

AbstractBackgroundA significant number of studies have investigated the use of blood-derived gene expression profiling as a biomarker for Alzheimer’s Disease (AD). However, the typical approach of developing classification models trained on subjects with AD and complimentary cognitive healthy controls may result in markers of general illness rather than being AD-specific. Incorporating additional related neurological and age-related disorders during the classification model development process may lead to the discovery of an AD-specific expression signature.MethodsTwo XGBoost classification models were developed and optimised. The first used the typical approach, training on 160 AD and 160 cognitively normal controls, while the second was trained in 6318 AD and 6318 mixed controls. Up-sampling was performed in each training set to the minority classes to avoid sampling bias, and both classification models were evaluated in an independent dataset consisting of 127 AD and 687 mixed controls. The mixed control group represents a heterogeneous ageing population consisting of Parkinson’s Disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, Bipolar Disorder, Schizophrenia, Coronary Artery Disease, Rheumatoid Arthritis, Chronic Obstructive Pulmonary Disease, and cognitively healthy subjects.ResultsThe typical approach resulted in a 74 gene classification model with a validation performance of 58.3% sensitivity, 30.3% specificity, 13.4% PPV and 79.7% NPV. In contrast, the second approach resulted in a 28 gene classification model with an overall improved validation performance of 46.5% sensitivity, 95.6% specificity, 66.3% PPV and 90.6% NPV.ConclusionsThe addition of related neurological and age-related disorders into the AD classification model developmental process identified a more AD-specific expression signature, with improved ability to distinguish AD from other related diseases and cognitively healthy controls. However, this was at the cost of sensitivity. Further improvement is still required to identify a robust blood transcriptomic signature specific to AD.

scholarly journals Epidemiological pathology of Aβ deposition in the ageing brain in CFAS: addition of multiple Aβ-derived measures does not improve dementia assessment using logistic regression and machine learning approaches

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
S. B. Wharton ◽  
◽  
D. Wang ◽  
C. Parikh ◽  
F. E. Matthews ◽  
...  
Keyword(s):  
Machine Learning ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Logistic Regression ◽  
Neuritic Plaque ◽  
Type I ◽  
Ageing Population ◽  
Braak Stage ◽  
Age Related ◽  
Highly Correlated

AbstractAβ-amyloid deposition is a key feature of Alzheimer’s disease, but Consortium to Establish a Registry for Alzheimer's Disease (CERAD) assessment, based on neuritic plaque density, shows a limited relationships to dementia. Thal phase is based on a neuroanatomical hierarchy of Aβ-deposition, and in combination with Braak neurofibrillary tangle staging also allows derivation of primary age-related tauopathy (PART). We sought to determine whether Thal Aβ phase predicts dementia better than CERAD in a population-representative cohort (n = 186) derived from the Cognitive Function and Ageing Study (CFAS). Cerebral amyloid angiopathy (CAA) was quantitied as the number of neuroanatomical areas involved and cases meeting criteria for PART were defined to determine if they are a distinct pathological group within the ageing population. Agreement with the Thal scheme was excellent. In univariate analysis Thal phase performed less well as a predictor of dementia than CERAD, Braak or CAA. Logistic regression, decision tree and linear discriminant analysis were performed for multivariable analysis, with similar results. Thal phase did not provide a better explanation of dementia than CERAD, and there was no additional benefit to including more than one assessment of Aβ in the model. Number of areas involved by CAA was highly correlated with assessment based on a severity score (p < 0.001). The presence of capillary involvement (CAA type I) was associated with higher Thal phase and Braak stage (p < 0.001). CAA was not associated with microinfarcts (p = 0.1). Cases satisfying pathological criteria for PART were present at a frequency of 10.2% but were not older and did not have a higher likelihood of dementia than a comparison group of individuals with similar Braak stage but with more Aβ. They also did not have higher hippocampal-tau stage, although PART was weakly associated with increased presence of thorn-shaped astrocytes (p = 0.048), suggesting common age-related mechanisms. Thal phase is highly applicable in a population-representative setting and allows definition of pathological subgroups, such as PART. Thal phase, plaque density, and extent and type of CAA measure different aspects of Aβ pathology, but addition of more than one Aβ measure does not improve dementia prediction, probably because these variables are highly correlated. Machine learning predictions reveal the importance of combining neuropathological measurements for the assessment of dementia.

scholarly journals Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer’s disease

2018 ◽  
Author(s):  
Stephen A. Semick ◽  
Rahul A. Bharadwaj ◽  
Leonardo Collado-Torres ◽  
Ran Tao ◽  
Joo Heon Shin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Brain Regions ◽  
Epigenetic Mechanism ◽  
Novel Genes ◽  
Age Related

AbstractBackgroundLate-onset Alzheimer’s disease (AD) is a complex age-related neurodegenerative disorder that likely involves epigenetic factors. To better understand the epigenetic state associated with AD represented as variation in DNA methylation (DNAm), we surveyed 420,852 DNAm sites from neurotypical controls (N=49) and late-onset AD patients (N=24) across four brain regions (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex and cerebellum).ResultsWe identified 858 sites with robust differential methylation, collectively annotated to 772 possible genes (FDR<5%, within 10kb). These sites were overrepresented in AD genetic risk loci (p=0.00655), and nearby genes were enriched for processes related to cell-adhesion, immunity, and calcium homeostasis (FDR<5%). We analyzed corresponding RNA-seq data to prioritize 130 genes within 10kb of the differentially methylated sites, which were differentially expressed and had expression levels associated with nearby DNAm levels (p<0.05). This validated gene set includes previously reported (e.g. ANK1, DUSP22) and novel genes involved in Alzheimer’s disease, such as ANKRD30B.ConclusionsThese results highlight DNAm changes in Alzheimer’s disease that have gene expression correlates, implicating DNAm as an epigenetic mechanism underlying pathological molecular changes associated with AD. Furthermore, our framework illustrates the value of integrating epigenetic and transcriptomic data for understanding complex disease.

scholarly journals Effects of Swimming Training and Royal Jelly on BDNF and NGF Gene Expression in Hippocampus Tissue of Rats with Alzheimer’s Disease

2020 ◽  
Vol 22 (2) ◽  
Author(s):  
Amin Dehbozorgi ◽  
Laleh Behbudi Tabrizi ◽  
Seyed Ali Hosseini ◽  
Masod Haj Rasoli
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Royal Jelly ◽  
Neurodegenerative Disorder ◽  
Control Group ◽  
Swimming Training ◽  
Age Related ◽  
And Training ◽  
Ngf Gene

Background: Alzheimer’s disease (AD) is an age-related neurodegenerative disorder. Evidence from neuropathological studies indicates that the levels of neurotrophins brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are compromised in AD. Objectives: The present study aimed to review the effects of swimming training and royal jelly (RJ) on BDNF and NGF gene expression in the hippocampus tissue of rats with AD. Methods: In the present experimental study, 25 rats with AD were divided into five groups, including (1) control, (2) sham, (3) RJ, (4) training, and (5) training with RJ. Five healthy rats were selected as the healthy control group to examine the effect of AD induction by 8 mg/kg trimethyltin chloride (TMT) intra-peritoneally on BDNF and NGF. During eight weeks, groups 3 and 5 received 100 mg/kg RJ daily intra-peritoneally, and groups 4 and 5 swam in a rat swimming tank three sessions per week. One-way ANOVA with Tukey’s post hoc test was used for data analysis in SPSS 20 software (P < 0.05). Results: The induction of AD by TMT had a significant effect on the reduction of BDNF (P = 0.001) and NGF (P = 0.001). However, RJ had a significant effect on the increase of NGF (P = 0.03). Nevertheless, RJ (P = 0.99), training (P = 0.99), and training with RJ (P = 0.94) had no significant effect on BDNF and training (P = 0.99) and training with RJ (P = 0.97) had no significant effect on NGF. Conclusions: It appears that RJ has a significant effect on the increase of NGF gene expression in the hippocampus tissue of rats with AD. Nevertheless, RJ consumption simultaneously with swimming training has no significant effect on BDNF and NGF.

A Qualitative Analysis Based on Relative Expression Orderings Identifies Transcriptional Subgroups for Alzheimer’s Disease

2020 ◽  
Vol 16 (13) ◽  
pp. 1175-1182 ◽  
Author(s):  
Guini Hong ◽  
Pengming Zeng ◽  
Na Li ◽  
Hao Cai ◽  
You Guo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Region ◽  
Expression Patterns ◽  
Brain Regions ◽  
Gene Expression Patterns ◽  
Relative Expression ◽  
Age Related ◽  
Relative Expression Orderings

Background: Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease. However, few studies have investigated the heterogeneous gene expression patterns in AD. Objective and Methods: We examined the gene expression patterns in four brain regions of AD based on the within-sample relative expression orderings (REOs). Gene pairs with significantly reversed REOs in AD samples compared to non-AD controls were identified for each brain region using Fisher’s exact test, and filtered according to their transcriptional differences between AD samples. Subgroups of AD were classified by cluster analysis. Results: REO-based gene expression profiling analyses revealed that transcriptional differences, as well as distinct disease subsets, existed within AD patients. For each brain region, two main subgroups were classified: one subgroup reported differentially expressed genes overlapped with the age-related genes, and the other might relate to neuroinflammation. Conclusion: AD transcriptional subgroups might help understand the underlying pathogenesis of AD, and lend support to a personalized approach to AD management.

Age-related changes in gene expression are accelerated in Alzheimer's disease

Synapse ◽  
2011 ◽  
Vol 65 (9) ◽  
pp. 971-974 ◽  
Author(s):  
P. Saetre ◽  
E. Jazin ◽  
L. Emilsson
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Age Related ◽  
Age Related Changes

scholarly journals Genotype-Phenotype Correlation of T Cell Subtypes Reveals Senescent and Cytotoxic Genes in Alzheimer's Disease

2021 ◽  
Author(s):  
Dallin Dressman ◽  
Thomas Buttrick ◽  
Maria Cimpean ◽  
David Bennett ◽  
Vilas Menon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
T Cells ◽  
T Cell ◽  
Rna Sequencing ◽  
Disease Risk ◽  
Synaptic Function ◽  
T Cell Subsets ◽  
Age Related

Recent studies identifying expression quantitative trait loci (eQTL) in immune cells have uncovered important links between disease risk alleles and gene expression trends in monocytes, T cells, and other cell types. However, these studies are generally done with young, healthy subjects, limiting the utility of their findings for age-related conditions such as Alzheimer's disease (AD). We have performed RNA sequencing on four T cell subsets in genome-wide genotyped and well-characterized AD subjects and age- and sex-matched healthy controls from the Religious Orders Study/Memory and Aging Project. Correlating gene expression data with AD neuropathological traits, and with single nucleotide polymorphisms (SNPs) to detect eQTLs, we identified several significant genes involved in T cell senescence and cytotoxicity, consistent with T cell RNA sequencing studies in aged/AD cohorts. We identified unexpected eQTLs previously associated with neuropsychiatric disease traits. Finally, we discovered that pathways related to axon guidance and synaptic function were enriched among trans-eQTLs in coding regions of the genome. Overall, our data sheds more light on the genetic basis behind phenotypic changes in T cells during aging and AD.

scholarly journals Cranial Manipulation Affects Cholinergic Pathway Gene Expression in an Animal Model of Age-related Cognitive Decline

2020 ◽  
Author(s):  
Ramu Anandakrishnan ◽  
Hope Tobey ◽  
Steven Nguyen ◽  
Osscar Gonzalez Sandoval ◽  
Bradley G. Klein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Nervous System ◽  
Cognitive Decline ◽  
Fold Change ◽  
Age Related ◽  
Age Dependent ◽  
Age Related Cognitive Decline

Abstract Age dependent dementia is a devastating disorder afflicting the growing older population around the world. Although pharmacological agents improve symptoms of dementia, age related co-morbidities combined with adverse effects often outweigh their clinical benefits. Therefore, non-pharmacological therapies are being investigated as an alternative. Randomized controlled trials and observational studies have shown promising results for cranial manipulation as a treatment for dementia and other nervous system disorders. In this study we examine the effect of osteopathic cranial manipulative medicine (OCMM) on gene expression, in an animal model for age-related cognitive decline (aged rats). We found that OCMM significantly affected the expression of 36 genes in the neuronal pathway (False Discovery Rate (FDR) < 0.004). The top five neuronal genes with the largest fold-change (Slc5a7, Chat, Slc18a3, Adcy5 and Cacna2d2, >2-fold change, FDR<0.004) are part of the cholinergic neurotransmission mechanism, which is known to affect cognitive function. Slc5a7, the highest overexpressed neuronal gene (3-fold change) encodes a sodium and chloride ion-dependent high-affinity transporter that mediates choline uptake for acetylcholine synthesis in cholinergic neurons. This is the pathway enhanced by the clinically used Alzheimer’s disease drug Donepezil, which selectively inhibits acetylcholinesterase, an enzyme that catalyzes endogenous acetylcholine degradation. In addition, 40% of significant differentially expressed (SDE) genes (FDR<0.004), have been previously implicated in neurological disorders. Overall, SDE genes and their role in central nervous system signaling pathways suggest a connection to previously reported OCMM induced behavioral and biochemical changes in rat models of age-dependent dementia. Further investigation in this direction will provide a better understanding of the molecular mechanisms of OCMM and its potential in clinical applications. With clinical validation, OCMM could represent a much needed low-risk adjunct treatment for age-related dementia including Alzheimer’s disease.

scholarly journals Largest GWAS (N=1,126,563) of Alzheimer’s Disease Implicates Microglia and Immune Cells

2020 ◽  
Author(s):  
Douglas P Wightman ◽  
Iris E Jansen ◽  
Jeanne E. Savage ◽  
Alexey A Shadrin ◽  
Shahram Bahrami ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Late Onset ◽  
Gene Expression Pattern ◽  
Human Microglia ◽  
Age Related ◽  
Causal Genes ◽  
Meta Analyses

SummaryLate-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases1. Late-onset Alzheimer’s disease is caused by a combination of many genetic variants with small effect sizes and environmental influences. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified2,3. Here we show that increased sample sizes allowed for identification of seven novel genetic loci contributing to Alzheimer’s disease. We highlighted eight potentially causal genes where gene expression changes are likely to explain the association. Human microglia were found as the only cell type where the gene expression pattern was significantly associated with the Alzheimer’s disease association signal. Gene set analysis identified four independent pathways for associated variants to influence disease pathology. Our results support the importance of microglia, amyloid and tau aggregation, and immune response in Alzheimer’s disease. We anticipate that through collaboration the results from this study can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants which contribute to Alzheimer’s pathology. Furthermore, the increased understanding of the mechanisms that mediate the effect of genetic variants on disease progression will help identify potential pathways and gene-sets as targets for drug development.

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