scholarly journals Complement receptor 1 gene (CR1) intragenic duplication and risk of Alzheimer’s disease

2018 ◽  
Author(s):  
Ezgi Kucukkilic ◽  
Keeley Brookes ◽  
Imelda Barber ◽  
Tamar Guetta-Baranes ◽  
Kevin Morgan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Complement Receptor ◽  
Ratio Test ◽  
Risk Haplotype ◽  
Single Nucleotide Variants ◽  
Specific Pcr ◽  
Increased Risk ◽  
Complement Receptor 1

AbstractSingle nucleotide variants (SNVs) within and surrounding the complement receptor 1 (CR1) gene show some of the strongest genome-wide association signals with late-onset Alzheimer’s disease. Some studies have suggested that this association signal is due to a duplication allele (CR1-B) of a low copy repeat (LCR) within the CR1 gene, which increases the number of complement C3b/C4b-binding sites in the mature receptor. In this study, we develop a triplex paralogue ratio test (PRT) assay for CR1 LCR copy number allowing large numbers of samples to be typed with a limited amount of DNA. We also develop a CR1-B allele-specific PCR based on the junction generated by an historical non-allelic homologous recombination event between CR1 LCRs. We use these methods to genotype CR1 and measure CR1-B allele frequency in both late-onset and early-onset cases and unaffected controls from the United Kingdom. Our data support an association of late-onset Alzheimer’s disease with the CR1-B allele, and confirm that this allele occurs most frequently on the risk haplotype defined by SNV alleles. Furthermore, regression models incorporating CR1-B genotype provide a bitter fit to our data compared to incorporating the SNP-defined risk haplotype, supporting the CR1-B allele as the variant underlying the increased risk of late-onset Alzheimer’s disease.

Complement receptor 1 polymorphisms and risk of late-onset Alzheimer's disease

2010 ◽  
Vol 1348 ◽  
pp. 216-221 ◽  
Author(s):  
Qun Zhang ◽  
Jin-Tai Yu ◽  
Qi-Xiu Zhu ◽  
Wei Zhang ◽  
Zhong-Chen Wu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Complement Receptor ◽  
Complement Receptor 1

scholarly journals Could Altered Evoked Pain Responsiveness Be a Phenotypic Biomarker for Alzheimer’s Disease Risk? A Cross-Sectional Analysis of Cognitively Healthy Individuals

2020 ◽  
pp. 1-7
Author(s):  
Raymond R. Romano ◽  
Michael A. Carter ◽  
Mary S. Dietrich ◽  
Ronald L. Cowan ◽  
Stephen P. Bruehl ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Healthy Subjects ◽  
Pain Sensitivity ◽  
Late Onset ◽  
Thermal Pain ◽  
Apoe4 Allele ◽  
Increased Risk ◽  
Pain Stimuli ◽  
Experimentally Induced

Background: This study evaluated whether the apolipoprotein ɛ4 (APOE4) allele, a genetic marker associated with increased risk of developing late-onset Alzheimer’s disease (AD), was associated with differences in evoked pain responsiveness in cognitively healthy subjects. Objective: The aim was to determine whether individuals at increased risk of late-onset AD based on APOE allele genotype differ phenotypically in their response to experimentally-induced painful stimuli compared to those who do not have at least one copy of the ɛ4 allele. Methods: Forty-nine cognitively healthy subjects aged 30–89 years old with the APOE4 allele (n = 12) and without (n = 37) were assessed for group differences in pain thresholds and affective (unpleasantness) responses to experimentally-induced thermal pain stimuli. Results: Statistically significant main effects of APOE4 status were observed for both the temperature at which three different pain intensity percepts were reached (p = 0.040) and the level of unpleasantness associated with each (p = 0.014). APOE4 positive participants displayed lower overall pain sensitivity than those who were APOE4 negative and also greater overall levels of pain unpleasantness regardless of intensity level. Conclusion: Cognitively healthy APOE4 carriers at increased risk of late-onset AD demonstrated reduced thermal pain sensitivity but greater unpleasantness to thermal pain stimuli relative to individuals at lower risk of late-onset AD. These results suggest that altered evoked pain perception could potentially be used as a phenotypic biomarker of late-onset AD risk prior to disease onset. Additional studies of this issue may be warranted.

scholarly journals Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

2019 ◽  
Vol 9 (10) ◽  
pp. 262 ◽  
Author(s):  
Hayden
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Type 2 Diabetes Mellitus ◽  
Late Onset ◽  
Neurovascular Unit ◽  
Age Related ◽  
Increased Risk

Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer’s disease–dementia (LOAD) are increasing in global prevalence and current predictions indicate they will only increase over the coming decades. These increases may be a result of the concurrent increases of obesity and aging. T2DM is associated with cognitive impairments and metabolic factors, which increase the cellular vulnerability to develop an increased risk of age-related LOAD. This review addresses possible mechanisms due to obesity, aging, multiple intersections between T2DM and LOAD and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db/db models are utilized to demonstrate marked cellular remodeling changes of mural and glia cells and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain’s neurovascular unit (NVU), neuroglia and neurons are presented. Five major intersecting links are considered: i. Aging (chronic age-related diseases); ii. metabolic (hyperglycemia advanced glycation end products and its receptor (AGE/RAGE) interactions and hyperinsulinemia-insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen–nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis—vascular stiffening and microvascular NVU/neuroglial remodeling) with resulting impaired cerebral blood flow.

Alzheimer's disease risk factor complement receptor 1 is associated with depression

2012 ◽  
Vol 510 (1) ◽  
pp. 6-9 ◽  
Author(s):  
Gillian Hamilton ◽  
Kathryn L. Evans ◽  
Donald J. MacIntyre ◽  
Ian J. Deary ◽  
Anna Dominiczak ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Disease Risk ◽  
Complement Receptor ◽  
Disease Risk Factor ◽  
Complement Receptor 1

scholarly journals Recent Consanguinity and Outbred Autozygosity Are Associated With Increased Risk of Late-Onset Alzheimer’s Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Valerio Napolioni ◽  
Marzia A. Scelsi ◽  
Raiyan R. Khan ◽  
Andre Altmann ◽  
Michael D. Greicius
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ethnic Groups ◽  
Late Onset ◽  
Population Increase ◽  
Outbred Population ◽  
Genotype Relative Risk ◽  
Subsequent Work ◽  
Sequencing Project ◽  
Increased Risk

Prior work in late-onset Alzheimer’s disease (LOAD) has resulted in discrepant findings as to whether recent consanguinity and outbred autozygosity are associated with LOAD risk. In the current study, we tested the association between consanguinity and outbred autozygosity with LOAD in the largest such analysis to date, in which 20 LOAD GWAS datasets were retrieved through public databases. Our analyses were restricted to eight distinct ethnic groups: African–Caribbean, Ashkenazi–Jewish European, European–Caribbean, French–Canadian, Finnish European, North-Western European, South-Eastern European, and Yoruba African for a total of 21,492 unrelated subjects (11,196 LOAD and 10,296 controls). Recent consanguinity determination was performed using FSuite v1.0.3, according to subjects’ ancestral background. The level of autozygosity in the outbred population was assessed by calculating inbreeding estimates based on the proportion (FROH) and the number (NROH) of runs of homozygosity (ROHs). We analyzed all eight ethnic groups using a fixed-effect meta-analysis, which showed a significant association of recent consanguinity with LOAD (N = 21,481; OR = 1.262, P = 3.6 × 10–4), independently of APOE∗4 (N = 21,468, OR = 1.237, P = 0.002), and years of education (N = 9,257; OR = 1.274, P = 0.020). Autozygosity in the outbred population was also associated with an increased risk of LOAD, both for FROH (N = 20,237; OR = 1.204, P = 0.030) and NROH metrics (N = 20,237; OR = 1.019, P = 0.006), independently of APOE∗4 [(FROH, N = 20,225; OR = 1.222, P = 0.029) (NROH, N = 20,225; OR = 1.019, P = 0.007)]. By leveraging the Alzheimer’s Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data, we determined that LOAD subjects do not show an enrichment of rare, risk-enhancing minor homozygote variants compared to the control population. A two-stage recessive GWAS using ADSP data from 201 consanguineous subjects in the discovery phase followed by validation in 10,469 subjects led to the identification of RPH3AL p.A303V (rs117190076) as a rare minor homozygote variant increasing the risk of LOAD [discovery: Genotype Relative Risk (GRR) = 46, P = 2.16 × 10–6; validation: GRR = 1.9, P = 8.0 × 10–4]. These results confirm that recent consanguinity and autozygosity in the outbred population increase risk for LOAD. Subsequent work, with increased samples sizes of consanguineous subjects, should accelerate the discovery of non-additive genetic effects in LOAD.

scholarly journals Abi3 regulates microglial ramification and dynamic tissue surveillance in vivo.

2021 ◽  
Author(s):  
Elena Simonazzi ◽  
Ruth Jones ◽  
Fangli Chen ◽  
Adam Ranson ◽  
Joshua Stevenson-Hoare ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Family ◽  
Family Member ◽  
Late Onset ◽  
Gene Family Member ◽  
Surveillance Activity ◽  
Increased Risk ◽  
Microglial Morphology

A rare coding variant of Abelson-interactor gene family member 3 (Abi3) is associated with increased risk of late-onset Alzheimer's Disease (AD). Although Abi3 is recognised as a core microglial gene, its role in microglia is largely unknown. Here we demonstrate that Abi3 is crucial for normal microglial morphology, distribution, and homeostatic tissue surveillance activity in vivo.

The Association between TREM2 Gene and Late-Onset Alzheimer’s Disease in Chinese Han Population

Gerontology ◽  
2021 ◽  
pp. 1-7
Author(s):  
Yan Sun ◽  
Yun-Ke Zhang ◽  
Hai Chen ◽  
Ren-Shou Chen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Logistic Regression ◽  
Regression Analysis ◽  
Environmental Factors ◽  
Logistic Regression Analysis ◽  
Late Onset ◽  
Increased Risk ◽  
The Impact ◽  
Load Risk

Objective: : The objective of this study was to evaluate the impact of single nucleotide polymorphisms (SNPs) in triggering receptor expressed on the myeloid cells 2 protein (TREM2) gene and their interaction with environmental factors and haplotypes on late-onset Alzheimer’s disease (LOAD). Methods: DNA was extracted from the whole blood of the participants and genotyped using PCR and followed by restriction fragment length polymorphism. The Hardy-Weinberg equilibrium test was used in the control group. Multivariate logistic regression analysis was used to determine the relationship between the 4 SNPs of the TREM2 gene and the risk of LOAD. Generalized multifactor dimensionality reduction was used to test the best interaction combination between SNPs and environmental factors. Results: Logistic regression analysis showed that the T allele of rs75932628 and the T allele of rs2234253 were independently associated with increased risk of LOAD, and adjusted odds ratios (ORs) were 1.81 (1.271–2.35) and 1.59 (1.15–2.03), respectively. However, there was no significant association with LOAD for rs142232675 and rs143332484. We found a best model significantly associated with LOAD risk that consisted of rs75932628 and smoking, which scored 10/10 for both the sign test and cross-validation consistency (p = 0.012). Stratified analysis indicated that current smokers with rs75932628-CT/TT genotype have the highest LOAD risk compared to never smokers with rs75932628 – CC genotype, OR (95% confidence interval) = 2.73 (1.72–3.79). Haplotypes of rs75932628 and rs2234253 were analyzed using the SHEsis online software. However, no haplotype was found to be significantly associated with the risk of LOAD. Conclusions: The T allele of rs75932628 and the T allele of rs2234253 and interaction between rs75932628 and smoking were all correlated with increased risk of LOAD.

Complement receptor 1 coding variant p.Ser1610Thr in Alzheimer's disease and related endophenotypes

2013 ◽  
Vol 34 (9) ◽  
pp. 2235.e1-2235.e6 ◽  
Author(s):  
Caroline Van Cauwenberghe ◽  
Karolien Bettens ◽  
Sebastiaan Engelborghs ◽  
Mathieu Vandenbulcke ◽  
Jasper Van Dongen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Complement Receptor ◽  
Complement Receptor 1

Polymorphisms of the cholesterol 24-hydroxylase (CYP46A1) gene and the risk of Alzheimer's disease in a Chinese population

2006 ◽  
Vol 18 (1) ◽  
pp. 37-45 ◽  
Author(s):  
Suk Ling Ma ◽  
Nelson Leung Sang Tang ◽  
Linda Chiu Wa Lam ◽  
Helen Fung Kum Chiu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Chinese Population ◽  
Haplotype Analysis ◽  
Cholesterol Metabolism ◽  
Essential Gene ◽  
Risk Haplotype ◽  
Increased Risk ◽  
The Brain ◽  
Chinese Subjects

Background: An increasing number of studies have suggested a link between cholesterol metabolism and Alzheimer's disease (AD), which may be mediated by its effect on amyloid processing. Intracranial cholesterol is primarily eliminated into the bloodstream through conversion into 24-hydroxycholesterol by the enzyme cholesterol 24-hydroxylase (encoded by the CYP46A1 gene). CYP46A1 is an essential gene modulating cholesterol metabolism in the brain.Method: To investigate whether polymorphisms in the CYP46A1 gene modulate the risk of AD, we studied four common polymorphisms (IVS1-192, IVS2-150, IVS3-128 and IVS4-122) in 182 Chinese AD patients and 179 age-matched healthy Chinese subjects.Results and conclusion: We found that the IVS3-128 polymorphism was associated with the risk of AD (p < 0.05). Subjects homozygous for the C alleles were protected from AD with an adjusted odds ratio (OR) of 1.53 [95% confidence interval (95% CI) 0.98–2.37, p = 0.047]. However, another minor allele, IVS1-192 C, was more prevalent in the AD group and was associated with an increased risk. Haplotype analysis revealed that two of the eight common haplotypes formed by the four polymorphisms were rarely found in the AD group, suggesting a protective effect of these two haplotypes (GTCA and CCTA). The results supported the involvement of the CYP46A1 gene and cholesterol metabolism in the pathogenesis of AD.

scholarly journals Peripheral complement interactions with amyloid β peptide in Alzheimer's disease: Polymorphisms, structure, and function of complement receptor 1

2018 ◽  
Vol 14 (11) ◽  
pp. 1438-1449 ◽  
Author(s):  
Jenny U. Johansson ◽  
William D. Brubaker ◽  
Harold Javitz ◽  
Andrew W. Bergen ◽  
Denise Nishita ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Structure And Function ◽  
Complement Receptor ◽  
Amyloid Β Peptide ◽  
Complement Receptor 1 ◽  
And Function
Sign in / Sign up

Export Citation Format

Share Document