scholarly journals Synchronized genetic activities in Alzheimer’s brains revealed by heterogeneity-capturing network analysis

2020 ◽  
Author(s):  
Sharlee Climer ◽  
Alan R. Templeton ◽  
Michael Garvin ◽  
Daniel Jacobson ◽  
Matthew Lane ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Heterogeneity ◽  
Complex Traits ◽  
Single Gene ◽  
Complex Trait ◽  
List Type ◽  
Correlation Measure ◽  
Computational Analyses ◽  
Combinatorial Interactions

AbstractIt is becoming increasingly evident that the efficacy of single-gene computational analyses for complex traits is nearly exhausted and future advances hinge on unraveling the intricate combinatorial interactions among multiple genes. However, the discovery of modules of genes working in concert to manifest a complex trait has been crippled by combinatorial complexity, genetic heterogeneity, and validation biases. We introduce Maestro, a novel network approach that employs a multifaceted correlation measure, which captures heterogeneity, and a rigorous validation method. Maestro’s utilization for Alzheimer’s disease (AD) reveals an expression pattern that has virtually zero probability of simultaneous expression by an individual, assuming independence. Yet this pattern is exhibited by 19.0% of AD cases and 7.3% of controls, establishing an unprecedented pattern of synchronized genetic activities in the human brain. This pattern is significantly associated with AD, with an odds ratio of 3.0. This study substantiates Maestro’s power for discovery of orchestrated genetic activities underlying complex traits. More generally, Maestro can be applied in diverse domains in which heterogeneity exists.HighlightsSynchronized genetic activities associated with Alzheimer’s diseaseNovel vector-based correlation measure that captures genetic heterogeneityEnhanced network model for revealing combinatorial genetic interactionsPro-survival genetic activities associated with Alzheimer’s diseaseGeneral approach for revealing patterns in data subject to heterogeneity

Genetic heterogeneity in Alzheimer's disease derived from five brain regions suggest new counteractions

2017 ◽  
Vol 381 ◽  
pp. 771
Author(s):  
Y.S. Peng ◽  
H. Chang ◽  
C.W. Tang ◽  
Y.Y. Peng ◽  
Y.H. Tein ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Heterogeneity ◽  
Brain Regions

scholarly journals Spatial inhibition of return is impaired in mild cognitive impairment and mild Alzheimer’s disease

2020 ◽  
Author(s):  
Xiong Jiang ◽  
James H. Howard ◽  
G. Wiliam Rebeck ◽  
R. Scott Turner
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Medial Temporal Lobe ◽  
Inhibition Of Return ◽  
Memory Performance ◽  
Brain Regions ◽  
List Type ◽  
Older Individuals

ABSTRACTSpatial inhibition of return (IOR) refers to the phenomenon by which individuals are slower to respond to stimuli appearing at a previously cued location compared to un-cued locations. Here we provide evidence supporting that spatial IOR is mildly impaired in individuals with mild cognitive impairment (MCI) or mild Alzheimer’s disease (AD), and the impairment is readily detectable using a novel double cue paradigm. Furthermore, reduced spatial IOR in high-risk healthy older individuals is associated with reduced memory and other neurocognitive task performance, suggesting that the novel double cue spatial IOR paradigm may be useful in detecting MCI and early AD.SIGNIFICANCE STATEMENTNovel double cue spatial inhibition of return (IOR) paradigm revealed a robust effect IOR deficits in individuals with mild cognitive impairment (MCI) or mild Alzheimer’s disease (AD)Spatial IOR effect correlates with memory performance in healthy older adults at a elevated risk of Alzheimer’s disease (with a family history or APOE e4 allele)The data suggests that double cue spatial IOR may be sensitive to detect early AD pathological changes, which may be linked to disease progress at the posterior brain regions (rather than the medial temporal lobe)

scholarly journals STIM1 deficiency is linked to Alzheimer’s disease and triggers cell death in SH-SY5Y cells by upregulation of L-type voltage-operated Ca2+ entry

2018 ◽  
Vol 96 (10) ◽  
pp. 1061-1079 ◽  
Author(s):  
Carlos Pascual-Caro ◽  
Maria Berrocal ◽  
Aida M. Lopez-Guerrero ◽  
Alberto Alvarez-Barrientos ◽  
Eulalia Pozo-Guisado ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Protein Expression ◽  
Transmembrane Domain ◽  
Neuroblastoma Cell ◽  
Disease Patient ◽  
List Type

Abstract STIM1 is an endoplasmic reticulum protein with a role in Ca2+ mobilization and signaling. As a sensor of intraluminal Ca2+ levels, STIM1 modulates plasma membrane Ca2+ channels to regulate Ca2+ entry. In neuroblastoma SH-SY5Y cells and in familial Alzheimer’s disease patient skin fibroblasts, STIM1 is cleaved at the transmembrane domain by the presenilin-1-associated γ-secretase, leading to dysregulation of Ca2+ homeostasis. In this report, we investigated expression levels of STIM1 in brain tissues (medium frontal gyrus) of pathologically confirmed Alzheimer’s disease patients, and observed that STIM1 protein expression level decreased with the progression of neurodegeneration. To study the role of STIM1 in neurodegeneration, a strategy was designed to knock-out the expression of STIM1 gene in the SH-SY5Y neuroblastoma cell line by CRISPR/Cas9-mediated genome editing, as an in vitro model to examine the phenotype of STIM1-deficient neuronal cells. It was proved that, while STIM1 is not required for the differentiation of SH-SY5Y cells, it is absolutely essential for cell survival in differentiating cells. Differentiated STIM1-KO cells showed a significant decrease of mitochondrial respiratory chain complex I activity, mitochondrial inner membrane depolarization, reduced mitochondrial free Ca2+ concentration, and higher levels of senescence as compared with wild-type cells. In parallel, STIM1-KO cells showed a potentiated Ca2+ entry in response to depolarization, which was sensitive to nifedipine, pointing to L-type voltage-operated Ca2+ channels as mediators of the upregulated Ca2+ entry. The stable knocking-down of CACNA1C transcripts restored mitochondrial function, increased mitochondrial Ca2+ levels, and dropped senescence to basal levels, demonstrating the essential role of the upregulation of voltage-operated Ca2+ entry through Cav1.2 channels in STIM1-deficient SH-SY5Y cell death. Key messages STIM1 protein expression decreases with the progression of neurodegeneration in Alzheimer’s disease. STIM1 is essential for cell viability in differentiated SH-SY5Y cells. STIM1 deficiency triggers voltage-regulated Ca2+ entry-dependent cell death. Mitochondrial dysfunction and senescence are features of STIM1-deficient differentiated cells.

Single Nucleotide Polymorphism and its Application in Mapping Loci Involved in Developing Human Diseases and Traits

2011 ◽  
pp. 113-127
Author(s):  
Rui-Ru Ji
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Complex Traits ◽  
Single Gene ◽  
Complex Trait ◽  
Human Diseases ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Systematic Analysis ◽  
Success Stories ◽  
Mapping Process

Common diseases or traits in humans are often influenced by complex interactions among multiple genes as well as environmental and lifestyle factors rather than being attributable to a genetic variation within a single gene. Identification of genes that confer disease susceptibility can be facilitated by studying DNA markers such as single nucleotide polymorphism (SNP) associated with a disease trait. Genome-wide association approaches offers a systematic analysis of the association of hundreds of thousands of SNPs with a quantitative complex trait. This method has been successfully applied to a wide variety of common human diseases and traits, and has generated valuable findings that have improved the understanding of the genetic basis of many complex traits. This chapter outlines the general mapping process and methods, highlights the success stories, and describes some limitations and challenges that lie ahead.

scholarly journals Genetic heterogeneity of Alzheimer’s disease in subjects with and without hypertension

GeroScience ◽  
2019 ◽  
Vol 41 (2) ◽  
pp. 137-154 ◽  
Author(s):  
Alireza Nazarian ◽  
Konstantin G. Arbeev ◽  
Arseniy P. Yashkin ◽  
Alexander M. Kulminski
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Heterogeneity

scholarly journals P1-130: HIGH-THROUGHPUT OMICS EXPLORER FOR ALZHEIMER'S DISEASE AND COMPLEX TRAITS GENETIC ANALYSIS

2019 ◽  
Vol 15 ◽  
pp. P285-P286
Author(s):  
Jorge Alberto Bahena ◽  
Fabiana H.G. Farias ◽  
Kathie A. Mihindukulasuriya ◽  
John P. Budde ◽  
Carlos Cruchaga ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Analysis ◽  
High Throughput ◽  
Complex Traits

Tests for genetic heterogeneity among 18 families with Alzheimer's disease

Neurology ◽  
1987 ◽  
Vol 37 (10) ◽  
pp. 1678-1678
Author(s):  
M. L. Marazita ◽  
M. A. Spence ◽  
A. Heyman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Heterogeneity

Genetic modulation of the senescent phenotype in Homo sapiens

Genome ◽  
1989 ◽  
Vol 31 (1) ◽  
pp. 390-397 ◽  
Author(s):  
George M. Martin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Heterogeneity ◽  
Homo Sapiens ◽  
Model Systems ◽  
Werner’S Syndrome ◽  
Senescent Phenotype ◽  
Werner's Syndrome ◽  
Progeroid Syndromes ◽  
Mutator Strains

While it is important to search for unifying mechanisms of aging among a variety of model systems, evolutionary arguments suggest that the pathophysiological details of senescence may be, to some extent, species specific. Moreover, in species that are characterized by extensive genetic heterogeneity, such as our own, one is likely to find kindreds with both "private" and "public" markers of aging. Crude estimates of the number of loci with the potential to modulate aspects of the senescent phenotype of man suggest that thousands of genes could be involved. No single locus appears to modulate all features. Some affect predominately a single aspect ("unimodal progeroid syndromes"); familial Alzheimer's disease is discussed as a prototype. Linkage studies indicate genetic heterogeneity for autosomal dominant forms of the disease. Some loci affect multiple aspects of the phenotype ("segmental progeroid disorders"); the prototype is Werner's syndrome, an autosomal recessive. Cells from homozygotes behave like mutator strains and undergo accelerated senescence in vitro. Elucidation of the biochemical genetic basis of such abiotrophic disorders may shed light on specific aging processes in man.Key words: Homo sapiens, senescence, progeroid syndromes, Alzheimer's disease, linkage, Werner's syndrome, mutator strains.

scholarly journals A Nelson-Aalen Estimate of the Incidence Rates of Early-Onset Alzheimer's Disease Associated with the Presenilin-1 Gene

2002 ◽  
Vol 32 (1) ◽  
pp. 1-42 ◽  
Author(s):  
Eng Hock Gui ◽  
Angus Macdonald
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Life Histories ◽  
Process Model ◽  
Single Gene ◽  
Later Life ◽  
Incidence Rates ◽  
Presenilin 1 ◽  
Early Onset Alzheimer’S Disease

AbstractWe analyse, in a probabilistic setting, Newcombe's (1981) life table method of estimating rates of onset of high-penetrance single-gene disorders, and extend this to a counting process model for individual life histories, including movement between risk groups arising from genetic testing and onset in relatives. A key result is that estimates of rates of onset at any age x must be conditioned only on information available when subjects were age x, even though their later life histories might be available to the investigator. This determines the data that must be included in pedigrees. We derive a Nelson-Aalen-type estimate of a function of the rate of onset, and show that when all that is known is that the persons in the study inherited a mutation with probability 1/2, the function estimated is bounded. In practice, the treatment of censored observations or the methods of ascertainment might cause the estimate to exceed this bound, which results in infinite estimates of the rate of onset but might be a useful diagnostic check on the presence of these features. We summarise the literature on mutations in the Presenilin-1 (PSEN-1) gene, associated with early-onset Alzheimer's disease (EOAD), and from published pedigrees we estimate rates of onset of EOAD.

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