scholarly journals Failure to detect synergy between variants in transferrin and hemochromatosis and Alzheimer’s disease in large cohort

2019 ◽  
Author(s):  
Elizabeth Vance ◽  
Josue Gonzalez ◽  
Justin B. Miller ◽  
Lindsey Staley ◽  
Paul K. Crane ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Statistical Power ◽  
Association Studies ◽  
Limited Sample ◽  
Epistatic Interactions ◽  
Hemochromatosis Gene ◽  
The Brain ◽  
And Oxidative Stress ◽  
Sufficient Statistical Power

AbstractAlzheimer’s disease (AD) is the most common cause of dementia and, despite decades of effort, there is no effective treatment. In the last decade, many association studies have identified genetic markers that are associated with AD status. Two of these studies suggest that an epistatic interaction between variants rs1049296 in the Transferrin (TF) gene and rs1800562 in the Homeostatic Iron Regulator (HFE) gene, commonly known as “the hemochromatosis gene”, is in genetic association with AD. TF and HFE are involved in the transport and regulation of iron in the brain, and disrupting these processes exacerbates AD pathology through increased neurodegeneration and oxidative stress. However, by using a significantly larger dataset from the Alzheimer’s Disease Genetics Consortium (ADGC), we fail to detect an association between TF rs1049296 or HFE rs1800562 with AD risk (TF rs1049296 p=0.38 and HFE rs1800562 p=0.40). In addition, logistic regression with an interaction term and a Synergy Factor Analysis (SFA) both failed to detect epistasis between TF rs1049296 and HFE rs1800562 (SF=0.94; p=0.48) in AD cases. Each of these analyses had sufficient statistical power (Power>0.99), suggesting that previously-reported associations may be the result of more complex epistatic interactions, genetic heterogeneity, or were false-positive associations due to limited sample sizes.

scholarly journals The Effect of a Traditional Preparation Containing Piper nigrum L. and Bunium persicum (Boiss.) B.Fedtsch. on Immobility Stress-Induced Memory Loss in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Marzieh Rashedinia ◽  
Mina Mojarad ◽  
Forouzan Khodaei ◽  
Ali Sahragard ◽  
Mohammad Javad Khoshnoud ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Motor Coordination ◽  
Black Pepper ◽  
Aqueous Extracts ◽  
Memory And Learning ◽  
Hydroalcoholic Extract ◽  
The Brain ◽  
And Oxidative Stress

Objective. Alzheimer’s disease is a progressive, age-related, and neurodegenerative disease characterized by mental decline. The exact cause of Alzheimer’s disease is unclear, but cholinergic dysfunction, protein accumulation, and oxidative stress are among the most important hypotheses. The main purpose of our study was to investigate the effects of aqueous and hydroalcoholic extract combination of these two medicinal plants, black pepper and cumin (as a related formulation in traditional Persian medicine), on memory and learning of an immobilized stress animal model. Methods. In this study, hydroalcoholic and aqueous extracts of cumin and black pepper fruits were prepared. Six groups of mice were treated orally for 2 weeks: control group, immobility stress, and stress-induced immobility mice received different doses of the hydroalcoholic extract (100 and 200 mg/kg) and aqueous extract (100 and 200 mg/kg). The shuttle box, novel object detection, and rotarod test were used to evaluate memory and learning. The activities of acetylcholinesterase, catalase (CAT), and superoxide dismutase (SOD) and the level of reduced glutathione (GSH) and malondialdehyde (MDA) were measured in the brain tissue. Results. Immobility stress significantly reduced learning and motor coordination. Furthermore, MDA levels and acetylcholinesterase activity were significantly increased, while CAT and SOD activities were significantly reduced in the brain of immobility-induced stress mice. Other findings indicated that hydroalcoholic and aqueous extracts (100 and 200 mg/kg) of cumin and black pepper fruits have an improving effect on animal motor coordination and learning ability, GSH content, and CAT, SOD, and acetylcholinesterase enzyme function in comparison with stress groups ( p < 0.05 ). Conclusion. The hydroalcoholic and aqueous extracts of cumin and black pepper fruits have protective effects against stress-induced memory deficit and oxidative stress and may have beneficial therapeutic effect in the treatment of neurodegenerative diseases.

scholarly journals Characterization of Brain Iron Deposition Pattern and Its Association With Genetic Risk Factor in Alzheimer’s Disease Using Susceptibility-Weighted Imaging

2021 ◽  
Vol 15 ◽  
Author(s):  
Peiting You ◽  
Xiang Li ◽  
Zhijiang Wang ◽  
Huali Wang ◽  
Bin Dong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Iron Deposition ◽  
Susceptibility Weighted Imaging ◽  
Normal Brain ◽  
Brain Iron ◽  
Brain Functions ◽  
The Brain ◽  
Brain Iron Deposition

The presence of iron is an important factor for normal brain functions, whereas excessive deposition of iron may impair normal cognitive function in the brain and lead to Alzheimer’s disease (AD). MRI has been widely applied to characterize brain structural and functional changes caused by AD. However, the effectiveness of using susceptibility-weighted imaging (SWI) for the analysis of brain iron deposition is still unclear, especially within the context of early AD diagnosis. Thus, in this study, we aim to explore the relationship between brain iron deposition measured by SWI with the progression of AD using various feature selection and classification methods. The proposed model was evaluated on a 69-subject SWI imaging dataset consisting of 24 AD patients, 21 mild cognitive impairment patients, and 24 normal controls. The identified AD progression-related regions were then compared with the regions reported from previous genetic association studies, and we observed considerable overlap between these two. Further, we have identified a new potential AD-related gene (MEF2C) closely related to the interaction between iron deposition and AD progression in the brain.

scholarly journals A novel age-informed approach for genetic association analysis in Alzheimer’s disease

2021 ◽  
Author(s):  
Yann Le Guen ◽  
Michael E. Belloy ◽  
Valerio Napolioni ◽  
Sarah J. Eger ◽  
Gabriel Kennedy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Logistic Regression ◽  
Genetic Association ◽  
Statistical Power ◽  
Cox Regression ◽  
Association Studies ◽  
Age At Onset ◽  
Simulated Data ◽  
Power Gain

ABSTRACTIntroductionMany Alzheimer’s disease (AD) genetic association studies disregard age or incorrectly account for it, hampering variant discovery.MethodUsing simulated data, we compared the statistical power of several models: logistic regression on AD diagnosis adjusted and not adjusted for age; linear regression on a score integrating case-control status and age; and multivariate Cox regression on age-at-onset. We applied these models to real exome-wide data of 11,127 sequenced individuals (54% cases) and replicated suggestive associations in 21,631 genotype-imputed individuals (51% cases).ResultsModelling variable AD risk across age results in 10-20% statistical power gain compared to logistic regression without age adjustment, while incorrect age adjustment leads to critical power loss. Applying our novel AD-age score and/or Cox regression, we discovered and replicated novel variants associated with AD on KIF21B, USH2A, RAB10, RIN3 and TAOK2 genes.DiscussionOur AD-age score provides a simple means for statistical power gain and is recommended for future AD studies.

scholarly journals Fast Algorithms for Conducting Large-Scale GWAS of Age-at-Onset Traits Using Cox Mixed-Effects Models

Genetics ◽  
2020 ◽  
Vol 215 (1) ◽  
pp. 41-58 ◽  
Author(s):  
Liang He ◽  
Alexander M. Kulminski
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Statistical Power ◽  
Large Scale ◽  
Cox Model ◽  
Association Studies ◽  
Age At Onset ◽  
Mixed Effects ◽  
Mixed Effects Models ◽  
Genome Wide Association Studies

Age-at-onset is one of the critical traits in cohort studies of age-related diseases. Large-scale genome-wide association studies (GWAS) of age-at-onset traits can provide more insights into genetic effects on disease progression and transitions between stages. Moreover, proportional hazards (or Cox) regression models can achieve higher statistical power in a cohort study than a case-control trait using logistic regression. Although mixed-effects models are widely used in GWAS to correct for sample dependence, application of Cox mixed-effects models (CMEMs) to large-scale GWAS is so far hindered by intractable computational cost. In this work, we propose COXMEG, an efficient R package for conducting GWAS of age-at-onset traits using CMEMs. COXMEG introduces fast estimation algorithms for general sparse relatedness matrices including, but not limited to, block-diagonal pedigree-based matrices. COXMEG also introduces a fast and powerful score test for dense relatedness matrices, accounting for both population stratification and family structure. In addition, COXMEG generalizes existing algorithms to support positive semidefinite relatedness matrices, which are common in twin and family studies. Our simulation studies suggest that COXMEG, depending on the structure of the relatedness matrix, is orders of magnitude computationally more efficient than coxme and coxph with frailty for GWAS. We found that using sparse approximation of relatedness matrices yielded highly comparable results in controlling false-positive rate and retaining statistical power for an ethnically homogeneous family-based sample. By applying COXMEG to a study of Alzheimer’s disease (AD) with a Late-Onset Alzheimer’s Disease Family Study from the National Institute on Aging sample comprising 3456 non-Hispanic whites and 287 African Americans, we identified the APOE ε4 variant with strong statistical power (P = 1e−101), far more significant than that reported in a previous study using a transformed variable and a marginal Cox model. Furthermore, we identified novel SNP rs36051450 (P = 2e−9) near GRAMD1B, the minor allele of which significantly reduced the hazards of AD in both genders. These results demonstrated that COXMEG greatly facilitates the application of CMEMs in GWAS of age-at-onset traits.

Advanced nanoparticular approaches to combat Alzheimer's disease

2021 ◽  
Vol 09 ◽  
Author(s):  
Rahul Shah ◽  
Sankha Bhattacharya
Keyword(s):  
Alzheimer’S Disease ◽  
Drug Delivery ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Ageing Population ◽  
Disease Therapy ◽  
Cns Penetration ◽  
The Brain ◽  
Improve Patient ◽  
And Oxidative Stress

: Alzheimer's disease (AD) is a neurological disease that affects many of the world's rapidly ageing population. In the etiology of Alzheimer’s disease (AD), the involvement of amyloid β (Aβ) plaque accumulation and oxidative stress in the brain have important roles. Various drugs have been proposed to prevent and treat AD, but delivering these therapeutic agents to the brain is difficult. Over the last decade, nanoparticle-mediated drug delivery represents one promising strategy to increase the CNS penetration of several therapeutic moieties successfully. Different nanocarriers are being investigated to treat and diagnose AD. NTDDS (nanotechnology-based drug delivery systems) can be used in various methods to improve patient compliance and treatment outcomes. However, literature analysis revealed that clinical activities such as NTDDS application in Alzheimer's disease research lag behind despite extensive research. This review gives an account of the BBB and discusses the literature on some drugs which are successfully encapsulated as nanoparticles for a future therapeutic approach. It also emphasizes the current clinical studies for Alzheimer's disease therapy.

Understanding the function of ABCA7 in Alzheimer's disease

2015 ◽  
Vol 43 (5) ◽  
pp. 920-923 ◽  
Author(s):  
Hongyun Li ◽  
Tim Karl ◽  
Brett Garner
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Chinese Hamster Ovary Cells ◽  
Amyloid Β ◽  
Mutant Form ◽  
Genome Wide Association Studies ◽  
App Processing ◽  
The Brain

ATP-binding cassette transporter A7 (ABCA7) is highly expressed in the brain. Recent genome-wide association studies (GWAS) identify ABCA7 single nt polymorphisms (SNPs) that increase Alzheimer's disease (AD) risk. It is now important to understand the true function of ABCA7 in the AD context. We have begun to address this using in vitro and in vivo AD models. Our initial studies showed that transient overexpression of ABCA7 in Chinese hamster ovary cells stably expressing human amyloid precursor protein (APP) resulted in an approximate 50% inhibition in the production of the AD-related amyloid-β (Aβ) peptide as compared with mock-transfected cells. This increased ABCA7 expression was also associated with alterations in other markers of APP processing and an accumulation of cellular APP. To probe for a function of ABCA7 in vivo, we crossed Abca7−/− mice with J20 mice, an amyloidogenic transgenic AD mouse model [B6.Cg-Tg(PDGFB-APPSwInd)20Lms/J] expressing a mutant form of human APP bearing both the Swedish (K670N/M671L) and Indiana (V717F) familial AD mutations. We found that ABCA7 loss doubled insoluble Aβ levels and amyloid plaques in the brain. This did not appear to be related to changes in APP processing (C-terminal fragment analysis), which led us to assess other mechanism by which ABCA7 may modulate Aβ homoeostasis. As we have shown that microglia express high levels of ABCA7, we examined a role for ABCA7 in the phagocytic clearance of Aβ. Our data indicated that the capacity for bone marrow-derived macrophages derived from Abca7−/− mice to phagocytose Aβ was reduced by 51% compared with wild-type (WT) mice. This suggests ABCA7 plays a role in the regulation of Aβ homoeostasis in the brain and that this may be related to Aβ clearance by microglia.

scholarly journals A novel age-informed approach for genetic association analysis in Alzheimer’s disease

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yann Le Guen ◽  
◽  
Michael E. Belloy ◽  
Valerio Napolioni ◽  
Sarah J. Eger ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Logistic Regression ◽  
Genetic Association ◽  
Statistical Power ◽  
Cox Regression ◽  
Association Studies ◽  
Age At Onset ◽  
Simulated Data ◽  
Power Gain

Abstract Background Many Alzheimer’s disease (AD) genetic association studies disregard age or incorrectly account for it, hampering variant discovery. Methods Using simulated data, we compared the statistical power of several models: logistic regression on AD diagnosis adjusted and not adjusted for age; linear regression on a score integrating case-control status and age; and multivariate Cox regression on age-at-onset. We applied these models to real exome-wide data of 11,127 sequenced individuals (54% cases) and replicated suggestive associations in 21,631 genotype-imputed individuals (51% cases). Results Modeling variable AD risk across age results in 5–10% statistical power gain compared to logistic regression without age adjustment, while incorrect age adjustment leads to critical power loss. Applying our novel AD-age score and/or Cox regression, we discovered and replicated novel variants associated with AD on KIF21B, USH2A, RAB10, RIN3, and TAOK2 genes. Conclusion Our AD-age score provides a simple means for statistical power gain and is recommended for future AD studies.

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