Polygenic hazard score: an enrichment marker for Alzheimer’s associated amyloid and tau deposition

Tan, Chin Hong; Fan, Chun Chieh; Mormino, Elizabeth C.; Sugrue, Leo P.; Broce, Iris; Hess, Christopher P.; Dillon, William P.; Bonham, Luke W.; Yokoyama, Jennifer S.; Karch, Celeste M.; Brewer, James B.; Rabinovici, Gil D.; Miller, Bruce L.; Schellenberg, Gerard D.; Kauppi, Karolina; Feldman, Howard; Holland, Dominic; McEvoy, Linda K.; Hyman, Bradley T.; Bennett, David A.; Andreassen, Ole A.; Dale, Anders M.; Desikan, Rahul S.

doi:10.1007/s00401-017-1789-4

Cited by 83 publications

(113 citation statements)

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“…For that reason, early detection is critical to prevent progression of the disease [5,6]. A combined screening approach that integrates biomarker, genomic, and clinical information will likely be required to optimize early identification and prevention of AD progression [7,8].…”

Section: Introductionmentioning

confidence: 99%

A/T/N polygenic risk score for cognitive decline in old age

Moore

Filshtein²,

Dumitrescu

et al. 2019

Preprint

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Research in Context Systematic ReviewAuthors reviewed relevant literature using PubMed and Google Scholar. Key studies that generated and validated polygenic risk scores (PRS) for clinical and pathologic AD were cited. PRS scores have been increasingly used in the literature but clinical utility continues to be questioned. InterpretationIn the current research landscape concerning PRS clinical utility in the AD space, there is room for model improvement and our hypothesis was that a PRS with integrated risk for AD biomarkers could yield a better model for cognitive decline. Future DirectionsThis study serves as proof-of-concept that encourages future study of integrated PRS across disease markers and utility in taking an A/T/N (amyloidosis, tauopathy and neurodegeneration) focused approach to genetic risk for cognitive decline and AD. Abstract INTRODUCTION: We developed a novel polygenic risk score (PRS) based on the A/T/N (amyloid plaques (A), phosphorylated tau tangles (T), and neurodegeneration (N)) framework and compared a PRS based on clinical AD diagnosis to assess which was a better predictor of cognitive decline. METHODS: We used summary statistics from genome wide association studies of cerebrospinal fluid amyloid-β (Aβ42) and phosphorylated-tau (ptau181), left hippocampal volume (LHIPV), and late-onset AD dementia to calculate PRS for 1181 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Individual PRS were averaged to generate a composite A/T/N PRS. We assessed the association of PRS with baseline and longitudinal cognitive composites of executive function and memory. RESULTS: The A/T/N PRS showed superior predictive performance on AD biomarkers and executive function decline compared to the clinical AD PRS. DISCUSSION: Results suggest that integration of genetic risk across AD biomarkers may improve prediction of disease progression. Boldface indicates P < 0.05. *P<1.25E-03 Bonferroni threshold. N=1,182 unless noted otherwise. No APOE denotes PRS excluding APOE region results. NC/MCI and NC indicate sensitivity analysis results with the denoted diagnostic groups (as assessed at baseline).

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Section: Introductionmentioning

confidence: 99%

A/T/N polygenic risk score for cognitive decline in old age

Moore

Filshtein²,

Dumitrescu

et al. 2019

Preprint

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“…Four studies excluded APOE and achieved AUC ranging from 0.57-0.75 [5,12,25,30]. Of those studies using time-to-event analysis, all four excluded APOE and reported hazard ratios (HR) ranging from 1.11-2.36 [23,35,70]. Of those studies using ORs, two included APOE in their PRS and reported OR ranging from 2.06-2.32 [12,34].…”

Section: Prediction Of Ad Case/control Statusmentioning

confidence: 99%

From Polygenic Scores to Precision Medicine in Alzheimer’s Disease: A Systematic Review

Harrison

Mistry

Muskett

et al. 2020

JAD

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Background: Late-onset Alzheimer's disease (AD) is highly heritable. The effect of many common genetic variants, single nucleotide polymorphisms (SNPs), confer risk. Variants are clustered in areas of biology, notably immunity and inflammation, cholesterol metabolism, endocytosis, and ubiquitination. Polygenic scores (PRS), which weight the sum of an individual's risk alleles, have been used to draw inferences about the pathological processes underpinning AD. Objective: This paper aims to systematically review how AD PRS are being used to study a range of outcomes and phenotypes related to neurodegeneration. Methods: We searched the literature from July 2008-July 2018 following PRISMA guidelines. Results: 57 studies met criteria. The AD PRS can distinguish AD cases from controls. The ability of AD PRS to predict conversion from mild cognitive impairment (MCI) to AD was less clear. There was strong evidence of association between AD PRS and cognitive impairment. AD PRS were correlated with a number of biological phenotypes associated with AD pathology, such as neuroimaging changes and amyloid and tau measures. Pathway-specific polygenic scores were also associated with AD-related biologically relevant phenotypes. Conclusion: PRS can predict AD effectively and are associated with cognitive impairment. There is also evidence of association between AD PRS and other phenotypes relevant to neurodegeneration. The associations between pathway specific polygenic scores and phenotypic changes may allow us to define the biology of the disease in individuals and indicate who may benefit from specific treatments. Longitudinal cohort studies are required to test the ability of PGS to delineate pathway-specific disease activity.

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“…PRS is constructed as a weighted sum of allele counts, where the weights are the B‐coefficients of SNP association with the disease obtained with the Logistic Regression (LR) analysis. Recent development of a polygenic hazard score (PHS) approach goes beyond AD risk prediction and provides prediction of individual age‐specific risk for developing AD . Prior to PHS analyses, Desikan et al .…”

Section: Introductionmentioning

confidence: 99%

Polygenic risk and hazard scores for Alzheimer's disease prediction

Leonenko

Sims

Shoai

et al. 2019

Ann Clin Transl Neurol

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Objective Genome‐wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age‐specific genetic risk for AD. The aim of this study was to quantify the age‐specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS. Methods Quantification of individual differences in age‐specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age‐specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P‐value thresholds for disease association. Results Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ≤ 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10−12) was observed for PRS based upon genome‐wide significant SNPs (P ≤ 5 × 10−8). The strength of association was weaker with less stringent SNP selection thresholds. Interpretation Both PRS and PHS can be used to predict an age‐specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ≤ 10−3, we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10−3, the age‐specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study).

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Polygenic hazard score: an enrichment marker for Alzheimer’s associated amyloid and tau deposition

Cited by 83 publications

References 30 publications

A/T/N polygenic risk score for cognitive decline in old age

A/T/N polygenic risk score for cognitive decline in old age

From Polygenic Scores to Precision Medicine in Alzheimer’s Disease: A Systematic Review

Polygenic risk and hazard scores for Alzheimer's disease prediction

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