scholarly journals Assessing genetic overlap and causality between blood plasma proteins and Alzheimer’s Disease

2021 ◽  
Author(s):  
Alex Handy ◽  
Jodie Lord ◽  
Rebecca Green ◽  
Jin Xu ◽  
Dag Aarsland ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Plasma ◽  
Plasma Proteins ◽  
Binding Protein ◽  
Risk Scores ◽  
P Value ◽  
Causal Pathway ◽  
Genetic Overlap ◽  
Blood Plasma Proteins

ABSTRACTBackground Blood plasma proteins are modifiable and have been associated with Alzheimer’s disease (AD), but understanding which proteins are on the causal pathway remains challenging.ObjectiveInvestigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian Randomization (MR).MethodsFollowing a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritised proteins with and without the apolipoprotein E region (APOE+/- PRS) and tested for association with AD status across three cohorts (n=6244). An AD PRS was also tested for association with protein levels in one cohort (n=410). Proteins showing association with AD were taken forward for MR.ResultsFor APOE e3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p-value <0.00017). No protein APOE-PRS or AD PRS (APOE+/-) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p-value=0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p-value=0.025, protein APOE-PRS p-value=0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the 5 proteins demonstrated a causal association (p-value<0.05) in either direction.ConclusionApolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, modifiable risk factor. Whilst evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power.

scholarly journals Assessing Genetic Overlap and Causality Between Blood Plasma Proteins and Alzheimer’s Disease

2021 ◽  
pp. 1-14
Author(s):  
Alex Handy ◽  
Jodie Lord ◽  
Rebecca Green ◽  
Jin Xu ◽  
Dag Aarsland ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Plasma ◽  
Plasma Proteins ◽  
Statistical Power ◽  
Binding Protein ◽  
Risk Scores ◽  
Causal Pathway ◽  
Genetic Overlap ◽  
Blood Plasma Proteins

Background: Blood plasma proteins have been associated with Alzheimer’s disease (AD), but understanding which proteins are on the causal pathway remains challenging. Objective: Investigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian randomization (MR). Methods: Following a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritized proteins with and without the apolipoprotein E region (APOE+/–PRS) and tested for association with AD status across three cohorts (n = 6,244). An AD PRS was also tested for association with protein levels in one cohort (n = 410). Proteins showing association with AD were taken forward for MR. Results: For APOE ɛ3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p <  0.00017). No protein APOE- PRS or AD PRS (APOE+/–) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p = 0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p = 0.025, protein APOE- PRS p = 0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the five proteins demonstrated a causal association (p <  0.05) in either direction. Conclusion: Apolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, accessible risk factor. While evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power.

scholarly journals Early Detection of Alzheimer's Disease with Blood Plasma Proteins Using Support Vector Machines

2021 ◽  
Vol 25 (1) ◽  
pp. 218-226
Author(s):  
Chima S. Eke ◽  
Emmanuel Jammeh ◽  
Xinzhong Li ◽  
Camille Carroll ◽  
Stephen Pearson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Support Vector Machines ◽  
Early Detection ◽  
Blood Plasma ◽  
Plasma Proteins ◽  
Support Vector ◽  
Vector Machines ◽  
Blood Plasma Proteins

The level of carbonylation of plasma proteins and peripheral blood leukocytes in patients with different duration of Alzheimer’s disease

2021 ◽  
pp. 235-243
Author(s):  
Petrov Dmitriy Sergeevich Petrov Dmitriy Sergeevich ◽  
Mariya Germanovna Engalycheva ◽  
Natalya Vasilievna Korotkova ◽  
Ulugbek Usmanovich Ochilov
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Plasma ◽  
Peripheral Blood ◽  
Plasma Proteins ◽  
Oxidative Modification ◽  
Mononuclear Leukocytes ◽  
Adaptive Potential ◽  
Oxidative Modification Of Proteins

The course of Alzheimer’s disease is associated with an increase in oxidative stress associated with an increase in the production of reactive oxygen species against the background of neurodegenerative inflammation, and a simultaneous depletion of the antioxidant defense capabilities of brain cells. The result is the oxidative modification of macromolecules: proteins, lipids, nucleic acids. Protein carbonylation products accumulate not only in neurons, and in direct correlation with the degree of increase in amyloidosis and neurodegeneration, but also in extra-neuronal tissues, including leukocytes. In the course of this study, the levels of spontaneous and induced oxidative modification of proteins were determined in the blood plasma and fractionated leukocytes of peripheral blood of patients with different durations of Alzheimer’s disease, and the value of the reserve-adaptive potential was assessed as markers of the severity of oxidative stress. It has been established that the course of Alzheimer’s disease has a greater effect on the accumulation of carbonyl derivatives in blood plasma. In patients with a disease duration of 5–10 years, the total level of aldehyde and ketone derivatives of modified plasma proteins exceeds the same indicator in subgroups with a shorter duration of the disease. This tendency is less typical for mononuclear leukocytes. The level of induced oxidative modification of proteins increases to a greater extent in blood plasma than in fractionated leukocytes. This indicates the depletion of the reserve-adaptive potential of plasma antioxidant capabilities, which is more pronounced in patients with a long course of Alzheimer’s disease. For polymorphonuclear leukocytes, such a pattern was not revealed, which is probably associated with a short cell life. In mononuclear leukocytes, as well as in plasma, there is a tendency to depletion of the reserve-adaptive potential, but to a lesser extent.

scholarly journals Identifying individuals with high risk of Alzheimer’s disease using polygenic risk scores is most accurate when using all genetic information.

2021 ◽  
Author(s):  
Ganna Leonenko ◽  
Emily Baker ◽  
Josua Stevenson-Hoare ◽  
Annerieke Sierksma ◽  
Mark Fiers ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Population Data ◽  
Risk Scores ◽  
P Value ◽  
Older Individuals ◽  
P Values ◽  
Polygenic Risk ◽  
Ε4 Allele ◽  
Polygenic Approach

Abstract There is little agreement regarding the approach and optimal p-value threshold of SNPs to calculate genetic risk scores for Alzheimer’s disease (AD). This reflects a fundamental underlying debate on the polygenic versus oligogenic disease architecture. We re-investigated the assumptions underlying the choice of specific p-value thresholds defining genetic loci used to determine polygenic risk scores (PRS). We find the optimal p-value threshold for SNP selection is 0.1, which supports the polygenic architecture of AD. We found that previous studies supporting an oligogenic model of AD did not take account of the reduction of APOE-ε4 allele frequency in older individuals, which skewed the results towards lower p-value thresholds and eclipsed the contribution of genes associated to AD with higher p-values. The polygenic approach to AD is also effective to identify individuals at high or low AD risk, when only APOE-ε3 homozygous individuals are considered. We also introduce the standardisation of PRS against a population data which ensures comparability of the PRS between studies. In conclusion, our work demonstrates that AD is fundamentally a polygenic disease and that stratifying populations for AD risk best takes the full PRS score into account.

scholarly journals Polygenic risk scores for Alzheimer’s disease, and academic achievement, cognitive and behavioural measures in children from the general population

2019 ◽  
Vol 48 (6) ◽  
pp. 1972-1980 ◽  
Author(s):  
Roxanna Korologou-Linden ◽  
Emma L Anderson ◽  
Hannah J Jones ◽  
George Davey Smith ◽  
Laura D Howe ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Academic Achievement ◽  
Educational Attainment ◽  
Biological Effects ◽  
Risk Scores ◽  
P Value ◽  
Childhood And Adolescence ◽  
Nucleotide Polymorphisms ◽  
Polygenic Risk

Abstract Objective Several studies report a polygenic component of risk for Alzheimer’s disease. Understanding whether this polygenic signal is associated with educational, cognitive and behavioural outcomes in children could provide an earlier window for intervention. Methods We examined whether polygenic risk scores (PRS) at varying P-value thresholds in children from the Avon Longitudinal Study of Parents and Children were associated with academic achievement, cognitive and behavioural measures in childhood and adolescence. Results We did not detect any evidence that the genome-wide significant PRS (5x10-8) were associated with these outcomes. PRS at the highest P-value threshold examined (P ≤ 5x10-1) were associated with lower academic achievement in adolescents (Key Stage 3; β: -0.03; 95% confidence interval: -0.05, -0.003) but the effect was attenuated when single nucleotide polymorphisms (SNPs) associated with educational attainment were removed. These PRS were associated with lower IQ (β: -0.04; 95% CI: -0.07, -0.02) at age 8 years with the effect remaining after removing SNPs associated with educational attainment. Conclusions SNPs mediating the biological effects of Alzheimer’s disease are unlikely to operate early in life. The evidence of association between PRS for Alzheimer’s disease at liberal thresholds and cognitive measures suggest shared genetic pathways between Alzheimer’s disease, academic achievement and cognition.

Post-Translational Oxidation Modifications of Blood Plasma Proteins of Cosmonauts after a Long-term Flight: Part I

2020 ◽  
Vol 46 (5) ◽  
pp. 531-539
Author(s):  
I. M. Larina ◽  
A. G. Brzhzovsky ◽  
A. M. Nosovsky ◽  
A. S. Kononikhin ◽  
O. I. Orlov
Keyword(s):  
Blood Plasma ◽  
Plasma Proteins ◽  
Blood Plasma Proteins

scholarly journals BIOPHYSICAL STUDIES OF BLOOD PLASMA PROTEINS

1946 ◽  
Vol 165 (1) ◽  
pp. 21-35 ◽  
Author(s):  
H.F. Deutsch ◽  
R.A. Alberty ◽  
L.J. Gosting
Keyword(s):  
Blood Plasma ◽  
Plasma Proteins ◽  
Biophysical Studies ◽  
Blood Plasma Proteins

scholarly journals Genetic Predisposition to Alzheimer’s Disease Is Associated with Enlargement of Perivascular Spaces in Centrum Semiovale Region

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 825
Author(s):  
Iacopo Ciampa ◽  
Grégory Operto ◽  
Carles Falcon ◽  
Carolina Minguillon ◽  
Manuel Castro de Moura ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Predisposition ◽  
Rating Scale ◽  
P Value ◽  
Perivascular Spaces ◽  
Centrum Semiovale ◽  
Logistic Regression Models ◽  
Visual Rating ◽  
Increased Risk

This study investigated whether genetic factors involved in Alzheimer’s disease (AD) are associated with enlargement of Perivascular Spaces (ePVS) in the brain. A total of 680 participants with T2-weighted MRI scans and genetic information were acquired from the ALFA study. ePVS in the basal ganglia (BG) and the centrum semiovale (CS) were assessed based on a validated visual rating scale. We used univariate and multivariate logistic regression models to investigate associations between ePVS in BG and CS with BIN1-rs744373, as well as APOE genotypes. We found a significant association of the BIN1-rs744373 polymorphism in the CS subscale (p value = 0.019; OR = 2.564), suggesting that G allele carriers have an increased risk of ePVS in comparison with A allele carriers. In stratified analysis by APOE-ε4 status (carriers vs. non-carriers), these results remained significant only for ε4 carriers (p value = 0.011; OR = 1.429). To our knowledge, the present study is the first suggesting that genetic predisposition for AD is associated with ePVS in CS. These findings provide evidence that underlying biological processes affecting AD may influence CS-ePVS.

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