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 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.

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.

scholarly journals The influence of the R47H TREM2 variant on microglial exosome profiles

2021 ◽  
Author(s):  
Anna Mallach ◽  
Johan Gobom ◽  
Henrik Zetterberg ◽  
John Hardy ◽  
Thomas M Piers ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Negative Regulation ◽  
Common Variant ◽  
Regulation Of Transcription ◽  
Phagocytic Cell ◽  
Increased Risk ◽  
Human Ipsc ◽  
Subsequent Addition

Abstract Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene are linked with an increased risk of dementia, in particular the R47Hhet  TREM2 variant is linked to late-onset Alzheimer’s disease. Using human iPSC-derived microglia, we assessed whether variations in the dynamics of exosome secretion, including their components, from these cells might underlie some of this risk. We found exosome size was not altered between common variant controls and R47Hhet variants, but the amount and constitution of exosomes secreted were different. Exosome quantities were rescued by incubation with an ATP donor or with lipids via a phosphatidylserine TREM2 ligand. Following a lipopolysaccharide or phagocytic cell stimulus, exosomes from common variant and R47Hhet microglia were found to contain cytokines, chemokines, APOE and TREM2. Differences were observed in the expression of CCL22, IL-1β and TREM2 between common variant and R47Hhet derived exosomes. Furthermore unlike common variant-derived exosomes, R47Hhet exosomes contained additional proteins linked to negative regulation of transcription and metabolic processes. Subsequent addition of exosomes to stressed neurones showed R47Hhet-derived exosomes to be less protective. These data have ramifications for the responses of microglia in Alzheimer’s disease and may point to further targets for therapeutic intervention.

scholarly journals Incidence of Epilepsy among elderly Sudanese patients with Alzheimer’s disease: A prospective cohort study on 480 patients, Khartoum, Sudan, 2019

2021 ◽  
Author(s):  
Abbasher Hussien Mohamed Ahmed ◽  
Khabab Abbasher Hussien Mohamed Ahmed ◽  
Mohammed Eltahier Abdalla Omer ◽  
Amira Siddig
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cohort Study ◽  
Prospective Cohort Study ◽  
Prospective Cohort ◽  
Late Onset ◽  
Brain Mri ◽  
Cerebral Atrophy ◽  
Incidence Rates ◽  
Increased Risk

Abstract Background: An increased prevalence of epilepsy had been documented with dementia. Alzheimer’s disease and epilepsy often coexist. Objective: The aim of this study to assess incidence rates of epilepsy among Sudanese patients with Alzheimer’s disease. Methods: This is a prospective cohort study. We followed 480 patients aged more than 65 years with diagnosis of Alzheimer’s disease between May 2006 and May 2019 looking for coexist epilepsy. Results: Regarding Alzheimer’s disease female were affected more than male (60%). 10% of our patients have epilepsy. Generalize epilepsy was the most common type (62%). Epilepsy was more common with late onset Alzheimer’s disease. Abnormal EEG was detected in 20% of our studied group. Abnormal Brain MRI in form of cerebral atrophy was observed in 60 % of patients with Alzheimer’s disease and epilepsy. Conclusion: Patients with Alzheimer’s disease have an increased risk of developing epilepsy. There is strong relation between disease duration and development of epilepsy.

scholarly journals Weighted burden analysis of exome-sequenced late onset Alzheimer’s cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK-3β and WNT signalling pathways

2019 ◽  
Author(s):  
David Curtis ◽  
Kaushiki Bakaya ◽  
Leona Sharma ◽  
Sreejan Bandyopadhyay
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rare Variants ◽  
Late Onset ◽  
Tyrosine Phosphatase ◽  
Sequencing Project ◽  
Functional Variants ◽  
Increase Risk ◽  
Gsk 3Β ◽  
Additional Support

SummaryPrevious studies have implicated common and rare genetic variants as risk factors for late onset Alzheimer’s disease (AD, LOAD). Here, weighted burden analysis was applied to over 10,000 exome sequenced subjects from the Alzheimer’s Disease Sequencing Project. Analyses were carried out to investigate whether rare variants predicted to have a functional effect within a gene were more commonly seen in cases or in controls. Confirmatory results were obtained for TREM2, ABCA7 and SORL1. Additional support was provided for PSEN1 (p = 0.0002), which previously had been only weakly implicated in LOAD. There was suggestive evidence that functional variants in PIK3R1, WNT7A, C1R and EXOC5 might increase risk and that variants in TIAF1 and/or NDRG2 might have a protective effect. Overall, there was strong evidence (p = 5 × 10−6) that variants in tyrosine phosphatase genes reduce the risk of developing LOAD. Since PIK3R1 variants are expected to impair PI3K/Akt/GSK-3β signalling while variants in tyrosine phosphatase genes would enhance it, these findings are in line with those from animal models suggesting that this pathway is protective against AD.

GSTO1*E155del polymorphism associated with increased risk for late-onset Alzheimer's disease: Association hypothesis for an uncommon genetic variant

2012 ◽  
Vol 506 (2) ◽  
pp. 203-207 ◽  
Author(s):  
Sara Piacentini ◽  
Renato Polimanti ◽  
Rosanna Squitti ◽  
Stefania Mariani ◽  
Simone Migliore ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variant ◽  
Late Onset ◽  
Disease Association ◽  
Increased Risk
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