scholarly journals Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer’s Disease

2016 ◽  
Vol 55 (2) ◽  
pp. 473-484 ◽  
Author(s):  
Burcu F. Darst ◽  
Rebecca L. Koscik ◽  
Annie M. Racine ◽  
Jennifer M. Oh ◽  
Rachel A. Krause ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Amyloid Β ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Increased Risk

Association Between Polygenic Risk Score and the Progression from Mild Cognitive Impairment to Alzheimer’s Disease

2021 ◽  
pp. 1-13
Author(s):  
Hongliang Liu ◽  
Michael Lutz ◽  
Sheng Luo ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Increased Risk ◽  
Risk Of Progression ◽  
Clinical Changes

Background: Mild cognitive impairment (MCI) is a heterogeneous condition and MCI patients are at increased risk of progression to dementia due to Alzheimer’s disease (AD). Objective: In this study, we aim to evaluate the associations between polygenic risk scores (PRSs) and 1) time to AD progression from MCI, 2) changes in longitudinal cognitive impairment, and 3) biomarkers from cerebrospinal fluid and imaging. Methods: We constructed PRS by using 40 independent non-APOE SNPs from well-replicated AD GWASs and tested its association with the progression time from MCI to AD by using 767 MCI patients from the ADNI study and 1373 patients from the NACC study. PRSs calculated with other methods were also computed. Results: We found that the PRS constructed with SNPs that reached genome-wide significance predicted the progression from MCI to AD (beta = 0.182, se = 0.061, p = 0.003) after adjusting for the demographic and clinical variables. This association was replicated in the NACC dataset (beta = 0.094, se = 0.037, p = 0.009). Further analyses revealed that PRS was associated with the increased ADAS-Cog11/ADAS-Cog13/ADASQ4 scores, tau/ptau levels, and cortical amyloid burdens (PIB and AV45), but decreased hippocampus and entorhinal cortex volumes (p <  0.05). Mediation analysis showed that the effect of PRS on the increased risk of AD may be mediated by Aβ 42 (beta = 0.056, SE = 0.026, p = 0.036). Conclusion: Our findings suggest that PRS can be useful for the prediction of time to AD and other clinical changes after the diagnosis of MCI.

The Differential Influence of Immune, Endocytotic, and Lipid Metabolism Genes on Amyloid Deposition and Neurodegeneration in Subjects at Risk of Alzheimer’s Disease

2021 ◽  
Vol 79 (1) ◽  
pp. 127-139
Author(s):  
Grazia Daniela Femminella ◽  
Denise Harold ◽  
James Scott ◽  
Julie Williams ◽  
Paul Edison ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipid Metabolism ◽  
Risk Score ◽  
Amyloid Deposition ◽  
Risk Scores ◽  
Healthy Controls ◽  
Cognitive Measures ◽  
Polygenic Risk ◽  
Increased Risk

Background: Over 20 single-nucleotide polymorphisms (SNPs) are associated with increased risk of Alzheimer’s disease (AD). We categorized these loci into immunity, lipid metabolism, and endocytosis pathways, and associated the polygenic risk scores (PRS) calculated, with AD biomarkers in mild cognitive impairment (MCI) subjects. Objective: The aim of this study was to identify associations between pathway-specific PRS and AD biomarkers in patients with MCI and healthy controls. Methods: AD biomarkers ([18F]Florbetapir-PET SUVR, FDG-PET SUVR, hippocampal volume, CSF tau and amyloid-β levels) and neurocognitive tests scores were obtained in 258 healthy controls and 451 MCI subjects from the ADNI dataset at baseline and at 24-month follow up. Pathway-related (immunity, lipid metabolism, and endocytosis) and total polygenic risk scores were calculated from 20 SNPs. Multiple linear regression analysis was used to test predictive value of the polygenic risk scores over longitudinal biomarker and cognitive changes. Results: Higher immune risk score was associated with worse cognitive measures and reduced glucose metabolism. Higher lipid risk score was associated with increased amyloid deposition and cortical hypometabolism. Total, immune, and lipid scores were associated with significant changes in cognitive measures, amyloid deposition, and brain metabolism. Conclusion: Polygenic risk scores highlights the influence of specific genes on amyloid-dependent and independent pathways; and these pathways could be differentially influenced by lipid and immune scores respectively.

scholarly journals Association between polygenic risk score of Alzheimer’s disease and plasma phosphorylated tau in individuals from the Alzheimer’s Disease Neuroimaging Initiative

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Anna Zettergren ◽  
◽  
Jodie Lord ◽  
Nicholas J. Ashton ◽  
Andrea L. Benedet ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Amyloid Β ◽  
Total Sample ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Tau Pathology ◽  
Polygenic Risk

Abstract Background Recent studies suggest that plasma phosphorylated tau181 (p-tau181) is a highly specific biomarker for Alzheimer’s disease (AD)-related tau pathology. It has great potential for the diagnostic and prognostic evaluation of AD, since it identifies AD with the same accuracy as tau PET and CSF p-tau181 and predicts the development of AD dementia in cognitively unimpaired (CU) individuals and in those with mild cognitive impairment (MCI). Plasma p-tau181 may also be used as a biomarker in studies exploring disease pathogenesis, such as genetic or environmental risk factors for AD-type tau pathology. The aim of the present study was to investigate the relation between polygenic risk scores (PRSs) for AD and plasma p-tau181. Methods Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was used to examine the relation between AD PRSs, constructed based on findings in recent genome-wide association studies, and plasma p-tau181, using linear regression models. Analyses were performed in the total sample (n = 818), after stratification on diagnostic status (CU (n = 236), MCI (n = 434), AD dementia (n = 148)), and after stratification on Aβ pathology status (Aβ positives (n = 322), Aβ negatives (n = 409)). Results Associations between plasma p-tau181 and APOE PRSs (p = 3e−18–7e−15) and non-APOE PRSs (p = 3e−4–0.03) were seen in the total sample. The APOE PRSs were associated with plasma p-tau181 in all diagnostic groups (CU, MCI, and AD dementia), while the non-APOE PRSs were associated only in the MCI group. The APOE PRSs showed similar results in amyloid-β (Aβ)-positive and negative individuals (p = 5e−5–1e−3), while the non-APOE PRSs were associated with plasma p-tau181 in Aβ positives only (p = 0.02). Conclusions Polygenic risk for AD including APOE was found to associate with plasma p-tau181 independent of diagnostic and Aβ pathology status, while polygenic risk for AD beyond APOE was associated with plasma p-tau181 only in MCI and Aβ-positive individuals. These results extend the knowledge about the relation between genetic risk for AD and p-tau181, and further support the usefulness of plasma p-tau181 as a biomarker of AD.

[P3-095]: THE USE OF POLYGENIC RISK SCORES (PRS) TO CHARACTERISE THE PRECLINICAL PHASE OF ALZHEIMER's DISEASE

2017 ◽  
Vol 13 (7S_Part_20) ◽  
pp. P970-P971
Author(s):  
Michelle K. Lupton ◽  
Margie Wright ◽  
Nick Martin ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Preclinical Phase

scholarly journals Associations between Alzheimer’s disease polygenic risk scores and hippocampal subfield volumes in 17,161 UK Biobank participants

2021 ◽  
Vol 98 ◽  
pp. 108-115
Author(s):  
Heidi Foo ◽  
Anbupalam Thalamuthu ◽  
Jiyang Jiang ◽  
Forrest Koch ◽  
Karen A. Mather ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Scores ◽  
Uk Biobank ◽  
Polygenic Risk

P3-482: HIGHER ALZHEIMER'S DISEASE POLYGENIC RISK SCORES ARE ASSOCIATED WITH GREATER OBJECTIVELY MEASURED COGNITIVE EFFORT DESPITE NORMAL NEUROPSYCHOLOGICAL FUNCTION

2006 ◽  
Vol 14 (7S_Part_24) ◽  
pp. P1305-P1306
Author(s):  
William S. Kremen ◽  
Matthew S. Panizzon ◽  
Eric L. Granholm ◽  
Jeremy A. Elman ◽  
Daniel E. Gustavson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Effort ◽  
Risk Scores ◽  
Neuropsychological Function ◽  
Polygenic Risk ◽  
Objectively Measured

scholarly journals Regional differences in Alzheimer’s disease pathology confound behavioural rescue after amyloid-β attenuation

Brain ◽  
2019 ◽  
Vol 143 (1) ◽  
pp. 359-373 ◽  
Author(s):  
Christopher D Morrone ◽  
Paolo Bazzigaluppi ◽  
Tina L Beckett ◽  
Mary E Hill ◽  
Margaret M Koletar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Function ◽  
Spatial Memory ◽  
Regional Differences ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Barnes Maze ◽  
Tau Pathology

Abstract Failure of Alzheimer’s disease clinical trials to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. To dissect contributions of individual pathologies to cognitive function, we used the TgF344-AD rat model, which recapitulates the salient hallmarks of Alzheimer’s disease pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). scyllo-Inositol treatment attenuated amyloid-β peptide in disease-bearing TgF344-AD rats, which rescued pattern separation in the novel object recognition task and executive function in the reversal learning phase of the Barnes maze. Interestingly, neither activities of daily living in the burrowing task nor spatial memory in the Barnes maze were rescued by attenuating amyloid-β peptide. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and in vivo electrophysiological signature of the hippocampus. Amyloid-β peptide attenuation reduced hippocampal tau pathology and rescued adult hippocampal neurogenesis and neuronal function, via improvements in cross-frequency coupling between theta and gamma bands. To investigate mechanisms underlying the persistence of spatial memory deficits, we next examined neuropathology in the entorhinal cortex, a region whose input to the hippocampus is required for spatial memory. Reduction of amyloid-β peptide in the entorhinal cortex had no effect on entorhinal tau pathology or entorhinal-hippocampal neuronal network dysfunction, as measured by an impairment in hippocampal response to entorhinal stimulation. Thus, rescue or not of cognitive function is dependent on regional differences of amyloid-β, tau and neuronal network dysfunction, demonstrating the importance of staging disease in patients prior to enrolment in clinical trials. These results further emphasize the need for combination therapeutic approaches across disease progression.

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