Using Polygenic Hazard Scores to Predict Age at Onset of Alzheimer’s Disease in Nordic Populations
Authors: Motazedi, Ehsan | Cheng, Weiqiu | Thomassen, Jesper Q. | Frei, Oleksandr | Rongve, Arvid | Athanasiu, Lavinia | Bahrami, Shahram | Shadrin, Alexey | Ulstein, Ingun | Stordal, Eystein | Brækhus, Anne | Saltvedt, Ingvild | Sando, Sigrid B. | O’Connell, Kevin S. | Hindley, Guy | van der Meer, Dennis | Bergh, Sverre | Nordestgaard, Børge G. | Tybjærg-Hansen, Anne | Bråthen, Geir | Pihlstrøm, Lasse | Djurovic, Srdjan | Frikke-Schmidt, Ruth | Fladby, Tormod | Aarsland, Dag | Selbæk, Geir | Seibert, Tyler M. | Dale, Anders M. | Fan, Chun C. | Andreassen, Ole A.
Article Type: Research Article
Abstract: Background: Polygenic hazard scores (PHS) estimate age-dependent genetic risk of late-onset Alzheimer’s disease (AD), but there is limited information about the performance of PHS on real-world data where the population of interest differs from the model development population and part of the model genotypes are missing or need to be imputed. Objective: The aim of this study was to estimate age-dependent risk of late-onset AD using polygenic predictors in Nordic populations. Methods: We used Desikan PHS model, based on Cox proportional hazards assumption, to obtain age-dependent hazard scores for AD from individual genotypes in the Norwegian DemGene cohort (n = 2,772). …We assessed the risk discrimination and calibration of Desikan model and extended it by adding new genotype markers (the Desikan Nordic model). Finally, we evaluated both Desikan and Desikan Nordic models in two independent Danish cohorts: The Copenhagen City Heart Study (CCHS) cohort (n = 7,643) and The Copenhagen General Population Study (CGPS) cohort (n = 10,886). Results: We showed a robust prediction efficiency of Desikan model in stratifying AD risk groups in Nordic populations, even when some of the model SNPs were missing or imputed. We attempted to improve Desikan PHS model by adding new SNPs to it, but we still achieved similar risk discrimination and calibration with the extended model. Conclusion: PHS modeling has the potential to guide the timing of treatment initiation based on individual risk profiles and can help enrich clinical trials with people at high risk to AD in Nordic populations. Show more
Keywords: Age at onset, Alzheimer’s disease, Nordic ancestry, polygenic hazard score
DOI: 10.3233/JAD-220174
Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1533-1544, 2022
Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer’s Disease Pathology
Authors: Shi, Liu | Winchester, Laura M. | Liu, Benjamine Y. | Killick, Richard | Ribe, Elena M. | Westwood, Sarah | Baird, Alison L. | Buckley, Noel J. | Hong, Shengjun | Dobricic, Valerija | Kilpert, Fabian | Franke, Andre | Kiddle, Steven | Sattlecker, Martina | Dobson, Richard | Cuadrado, Antonio | Hye, Abdul | Ashton, Nicholas J. | Morgan, Angharad R. | Bos, Isabelle | Vos, Stephanie J.B. | ten Kate, Mara | Scheltens, Philip | Vandenberghe, Rik | Gabel, Silvy | Meersmans, Karen | Engelborghs, Sebastiaan | De Roeck, Ellen E. | Sleegers, Kristel | Frisoni, Giovanni B. | Blin, Olivier | Richardson, Jill C. | Bordet, Régis | Molinuevo, José L. | Rami, Lorena | Wallin, Anders | Kettunen, Petronella | Tsolaki, Magda | Verhey, Frans | Lleó, Alberto | Alcolea, Daniel | Popp, Julius | Peyratout, Gwendoline | Martinez-Lage, Pablo | Tainta, Mikel | Johannsen, Peter | Teunissen, Charlotte E. | Freund-Levi, Yvonne | Frölich, Lutz | Legido-Quigley, Cristina | Barkhof, Frederik | Blennow, Kaj | Rasmussen, Katrine Laura | Nordestgaard, Børge Grønne | Frikke-Schmidt, Ruth | Nielsen, Sune Fallgaard | Soininen, Hilkka | Vellas, Bruno | Kloszewska, Iwona | Mecocci, Patrizia | Zetterberg, Henrik | Morgan, B. Paul | Streffer, Johannes | Visser, Pieter Jelle | Bertram, Lars | Nevado-Holgado, Alejo J. | Lovestone, Simon
Article Type: Research Article
Abstract: Background: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer’s disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. Objective: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. Methods: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature …induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). Results: We identified a 100-protein signature induced by DKK1 in vitro . Subsets of proteins, along with age and apolipoprotein E ɛ 4 genotype distinguished amyloid pathology (A + T–N–, A+T+N–, A+T–N+, and A+T+N+) from no AD pathology (A–T–N–) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. Conclusions: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo . Show more
Keywords: ATN framework, Dickkopf-1, replication, SomaScan, Wnt signaling
DOI: 10.3233/JAD-200208
Citation: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1353-1368, 2020