APOE Missense Variant R145C is Associated with Increased Alzheimer's Disease Risk in African Ancestry Individuals with the APOE Ε3/Ε4 Genotype

2021 ◽  
Author(s):  
Yann Le Guen ◽  
Michael E. Belloy ◽  
Sarah J. Eger ◽  
Annabel Chen ◽  
Gabriel Kennedy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Risk ◽  
African Ancestry ◽  
Missense Variant

ABCA7, a Genetic Risk Factor Associated with Alzheimer’s Disease Risk in African Americans

2022 ◽  
pp. 1-15
Author(s):  
Kaitlyn E. Stepler ◽  
Taneisha R. Gillyard ◽  
Calla B. Reed ◽  
Tyra M. Avery ◽  
Jamaine S. Davis ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
African American ◽  
Amyloid Beta ◽  
Disease Risk ◽  
African Ancestry ◽  
European Ancestry ◽  
Black Adults ◽  
American Black ◽  
The Impact

African American/Black adults are twice as likely to have Alzheimer’s disease (AD) compared to non-Hispanic White adults. Genetics partially contributes to this disparity in AD risk, among other factors, as there are several genetic variants associated with AD that are more prevalent in individuals of African or European ancestry. The phospholipid-transporting ATPase ABCA7 (ABCA7) gene has stronger associations with AD risk in individuals with African ancestry than in individuals with European ancestry. In fact, ABCA7 has been shown to have a stronger effect size than the apolipoprotein E (APOE) ɛ4 allele in African American/Black adults. ABCA7 is a transmembrane protein involved in lipid homeostasis and phagocytosis. ABCA7 dysfunction is associated with increased amyloid-beta production, reduced amyloid-beta clearance, impaired microglial response to inflammation, and endoplasmic reticulum stress. This review explores the impact of ABCA7 mutations that increase AD risk in African American/Black adults on ABCA7 structure and function and their contributions to AD pathogenesis. The combination of biochemical/biophysical and ‘omics-based studies of these variants needed to elucidate their downstream impact and molecular contributions to AD pathogenesis is highlighted.

scholarly journals Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer’s disease

2018 ◽  
Author(s):  
Nisha Rathore ◽  
Sree Ranjani Ramani ◽  
Homer Pantua ◽  
Jian Payandeh ◽  
Tushar Bhangale ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Cell ◽  
Disease Risk ◽  
Missense Variant ◽  
Cell Types ◽  
Glycoprotein B ◽  
Receptor Alpha ◽  
Hsv 1

AbstractPaired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) is a cell surface inhibitory receptor that recognizes specific O-glycosylated proteins and is expressed on various innate immune cell types including microglia. We show here that a common missense variant (G78R, rs1859788) of PILRA is the likely causal allele for the confirmed Alzheimer’s disease risk locus at 7q21 (rs1476679). The G78R variant alters the interaction of residues essential for sialic acid engagement, resulting in >50% reduced binding for several PILRA ligands including a novel ligand, complement component 4A, and herpes simplex virus 1 (HSV-1) glycoprotein B. PILRA is an entry receptor for HSV-1 via glycoprotein B, and macrophages derived from R78 homozygous donors showed significantly decreased levels of HSV-1 infection at several multiplicities of infection compared to homozygous G78 macrophages. We propose that PILRA G78R protects individuals from Alzheimer’s disease risk via reduced inhibitory signaling in microglia and reduced microglial infection during HSV-1 recurrence.

scholarly journals APOE missense variant R145C is associated with increased Alzheimer's disease risk in African ancestry individuals with the APOE ϵ3/ϵ4 genotype

2021 ◽  
Author(s):  
Yann Le Guen ◽  
Michael E Belloy ◽  
Sarah J Eger ◽  
Annabel Chen ◽  
Gabriel Kennedy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
African Ancestry ◽  
Age At Onset ◽  
Missense Variant ◽  
Competing Risk ◽  
Next Generation Sequencing Data ◽  
Increased Risk

BACKGROUND The APOE gene has two common missense variants that greatly impact the risk of late-onset Alzheimer's disease (AD). Here we examined the risk of a third APOE missense variant, R145C, that is rare in European-Americans but present in 4% of African-Americans and always in phase with APOE ϵ3. METHODS In this study, we included 11,790 individuals of African and Admixed-African ancestry (4,089 cases and 7,701 controls). The discovery sample was composed of next generation sequencing data (2,888 cases and 4,957 controls), and the replication was composed of microarray data imputed on the TOPMed reference panel (1,201 cases and 2,744 contols). To assess the effect of R145C independently of the ϵ2 and ϵ4 alleles, we performed stratified analyses in ϵ2/ϵ3, ϵ3/ϵ3, and ϵ3/ϵ4 subjects. In primary analyses, the AD risk associated with R145C was estimated using a linear mixed model regression on case-control diagnosis. In secondary analyses, we estimated the influence of R145C on age-at-onset using linear-mixed-model regression, and risk of conversion to AD using competing risk regression. RESULTS In ϵ3/ϵ4-stratified meta-analyses, R145C carriers had an almost three-fold increased risk compared to non-carriers (odds ratio, 2.75; 95% confidence interval [CI], 1.84 to 4.11; P = 8.3x10-7) and had a reported AD age-at-onset almost 6 years younger (β, -5.72; 95% CI, 7.87 to -3.56; P = 2.0x10-7). Competing risk regression showed that the cumulative incidence of AD grows faster with age in R145C carriers compared to non-carriers (hazard ratio, 2.42, 95% CI, 1.81 to 3.25; P = 3.7x10-9). CONCLUSION The R145C variant is a potent risk factor for AD among African ancestry individuals with the ϵ3/ϵ4 genotype. Our findings should enhance AD risk prediction in African ancestry individuals and help elucidate the mechanisms linking the apoE protein to AD pathogenesis. The findings also add to the growing body of evidence demonstrating the importance of including ancestrally-diverse populations in genetic studies.

scholarly journals MAPT H1 Haplotype is Associated with Late-Onset Alzheimer’s Disease Risk in APOE ɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium

2015 ◽  
Vol 49 (2) ◽  
pp. 343-352 ◽  
Author(s):  
Pau Pastor ◽  
Fermín Moreno ◽  
Jordi Clarimón ◽  
Agustín Ruiz ◽  
Onofre Combarros ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Risk ◽  
Late Onset

scholarly journals A multilayer multimodal detection and prediction model based on explainable artificial intelligence for Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shaker El-Sappagh ◽  
Jose M. Alonso ◽  
S. M. Riazul Islam ◽  
Ahmad M. Sultan ◽  
Kyung Sup Kwak
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cross Validation ◽  
Disease Risk ◽  
Binary Classification ◽  
Fuzzy Rule ◽  
Large Set ◽  
Detection Model ◽  
Multi Class Classification ◽  
Clinical Measures

AbstractAlzheimer’s disease (AD) is the most common type of dementia. Its diagnosis and progression detection have been intensively studied. Nevertheless, research studies often have little effect on clinical practice mainly due to the following reasons: (1) Most studies depend mainly on a single modality, especially neuroimaging; (2) diagnosis and progression detection are usually studied separately as two independent problems; and (3) current studies concentrate mainly on optimizing the performance of complex machine learning models, while disregarding their explainability. As a result, physicians struggle to interpret these models, and feel it is hard to trust them. In this paper, we carefully develop an accurate and interpretable AD diagnosis and progression detection model. This model provides physicians with accurate decisions along with a set of explanations for every decision. Specifically, the model integrates 11 modalities of 1048 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) real-world dataset: 294 cognitively normal, 254 stable mild cognitive impairment (MCI), 232 progressive MCI, and 268 AD. It is actually a two-layer model with random forest (RF) as classifier algorithm. In the first layer, the model carries out a multi-class classification for the early diagnosis of AD patients. In the second layer, the model applies binary classification to detect possible MCI-to-AD progression within three years from a baseline diagnosis. The performance of the model is optimized with key markers selected from a large set of biological and clinical measures. Regarding explainability, we provide, for each layer, global and instance-based explanations of the RF classifier by using the SHapley Additive exPlanations (SHAP) feature attribution framework. In addition, we implement 22 explainers based on decision trees and fuzzy rule-based systems to provide complementary justifications for every RF decision in each layer. Furthermore, these explanations are represented in natural language form to help physicians understand the predictions. The designed model achieves a cross-validation accuracy of 93.95% and an F1-score of 93.94% in the first layer, while it achieves a cross-validation accuracy of 87.08% and an F1-Score of 87.09% in the second layer. The resulting system is not only accurate, but also trustworthy, accountable, and medically applicable, thanks to the provided explanations which are broadly consistent with each other and with the AD medical literature. The proposed system can help to enhance the clinical understanding of AD diagnosis and progression processes by providing detailed insights into the effect of different modalities on the disease risk.

scholarly journals The BIN1 rs744373 Alzheimer's disease risk SNP is associated with faster Aβ‐associated tau accumulation and cognitive decline

2021 ◽  
Author(s):  
Nicolai Franzmeier ◽  
Rik Ossenkoppele ◽  
Matthias Brendel ◽  
Anna Rubinski ◽  
Ruben Smith ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Disease Risk
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