Risk of dementia in APOE ε4 carriers is mitigated by a polygenic risk score.

Autor: Ebenau JL; Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands., van der Lee SJ; Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands.; Department of Clinical Genetics Amsterdam UMC Amsterdam the Netherlands., Hulsman M; Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands.; Department of Clinical Genetics Amsterdam UMC Amsterdam the Netherlands.; Delft Bioinformatics Lab Delft University of Technology Delft the Netherlands., Tesi N; Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands.; Department of Clinical Genetics Amsterdam UMC Amsterdam the Netherlands.; Delft Bioinformatics Lab Delft University of Technology Delft the Netherlands., Jansen IE; Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands.; Department of Complex Trait Genetics Center for Neurogenomics and Cognitive Research Amsterdam Neuroscience VU University Amsterdam the Netherlands., Verberk IMW; Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands.; Neurochemistry Laboratory Department of Clinical Chemistry Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands., van Leeuwenstijn M; Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands., Teunissen CE; Neurochemistry Laboratory Department of Clinical Chemistry Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands., Barkhof F; Department of Radiology & Nuclear Medicine Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands.; Queen Square Institute of Neurology and Centre for Medical Image Computing University College London London UK., Prins ND; Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands., Scheltens P; Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands., Holstege H; Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands.; Department of Clinical Genetics Amsterdam UMC Amsterdam the Netherlands.; Delft Bioinformatics Lab Delft University of Technology Delft the Netherlands., van Berckel BNM; Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands.; Department of Radiology & Nuclear Medicine Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands., van der Flier WM; Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands.; Department of Epidemiology and Biostatistics Amsterdam UMC Amsterdam the Netherlands.
Jazyk: angličtina
Zdroj: Alzheimer's & dementia (Amsterdam, Netherlands) [Alzheimers Dement (Amst)] 2021 Sep 14; Vol. 13 (1), pp. e12229. Date of Electronic Publication: 2021 Sep 14 (Print Publication: 2021).
DOI: 10.1002/dad2.12229
Abstrakt: Introduction: We investigated relationships among genetic determinants of Alzheimer's disease (AD), amyloid/tau/neurodegenaration (ATN) biomarkers, and risk of dementia.
Methods: We studied cognitively normal individuals with subjective cognitive decline (SCD) from the Amsterdam Dementia Cohort and SCIENCe project. We examined associations between genetic variants and ATN biomarkers, and evaluated their predictive value for incident dementia. A polygenic risk score (PRS) was calculated based on 39 genetic variants. The APOE gene was not included in the PRS and was analyzed separately.
Results: The PRS and APOE ε4 were associated with amyloid-positive ATN profiles, and APOE ε4 additionally with isolated increased tau (A-T+N-). A high PRS and APOE ε4 separately predicted AD dementia. Combined, a high PRS increased while a low PRS attenuated the risk associated with ε4 carriers.
Discussion: Genetic variants beyond APOE are clinically relevant and contribute to the pathophysiology of AD. In the future, a PRS might be used in individualized risk profiling.
Competing Interests: Jarith L. Ebenau, Sven J. van der Lee, Marc Hulsman, Niccolò Tesi, Iris E. Jansen, Inge M.W. Verberk, and Mardou van Leeuwenstijn report no conflicts of interest. Charlotte E. Teunissen serves on the advisory board of Roche; performed contract research or received grants from AC‐Immune, ADxNeurosciences, Boehringer, Brainstorm Therapeutics, Celgene, EIP Pharma, PeopleBio, Vivoryon, Roche, Toyama Fujifilm, Esai, and Probiodrug; and received lecture fees from Biogen and Axon Neurosciences. Her research is supported by the European Commission (Marie Curie International Training Network, and JPND), Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, Alzheimer Association. CT is recipient of ABOARD, which is a public–private partnership receiving funding from ZonMW and Health∼Holland, Topsector Life Sciences & Health. ABOARD also receives funding from Edwin Bouw Fonds and Gieskes‐Strijbis fonds. CT has a collaboration contract with ADx Neurosciences and Quanterix. CT is editor at Alzheimer's Research & Therapy, Neurology: Neuroimmunology & Neuroinflammation and Medidact Neurology, and edited a volume in the series Neuromethods (Springer). Frederik Barkhof is a consultant for Biogen‐Idec, Bayer‐Schering, Merck‐Serono, Roche, NovartisIXICO, and Combinostics; has received sponsoring from European Commission‐Horizon 2020, National Institute for Health Research‐University College London Hospitals Biomedical Research Centre, TEVA, Novartis, and Biogen; and serves on the editorial boards of Radiology, Brain, Neuroradiology, Multiple Sclerosis Journal, and Neurology. Niels D. Prins is consultant to Boehringer Ingelheim, Aribio, and Amylyx. He is co‐PI of a study with Fuji Film Toyama Chemical. He serves on the DSMB of Abbvie's M15‐566 trial. NP has received a speaker fee from Biogen. Payments were made to his company. He is CEO and co‐owner of the Brain Research Center, the Netherlands. Philip Scheltens has acquired grant support (for the institution) from Biogen. In the past two years, he has received consultancy/speaker fees (paid to the institution) from Probiodrug Biogen, EIP Pharma, Merck AG. Henne Holstege received funding from Aegon, Health ∼ Holland, Hans und Ilse Breuer Stiftung, JPND research, 100‐plus enabling, and Alzheimer Nederland. All funding is paid to her institution. Bart N.M. van Berckel has received funding from ZonMW, the Netherlands Organization of Scientific Research, the Centre of Translational Molecular Imaging, and Avid Radiopharmaceuticals. All funding is paid to his institution. Wiesje M. van der Flier Research programs have been funded by ZonMW, NWO, EU‐FP7, EU‐JPND, Alzheimer Nederland, CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes‐Strijbis fonds, stichting Equilibrio, Pasman stichting, Biogen MA Inc, Boehringer Ingelheim, Life‐MI, AVID, Roche BV, Fujifilm, Combinostics. WF holds the Pasman chair. WF has performed contract research for Biogen MA Inc and Boehringer Ingelheim. WF has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc, Danone, Eisai, and WebMD Neurology (Medscape). WF is consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. WF is associate editor at Alzheimer's Research & Therapy. All funding is paid to her institution.
(© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)
Databáze: MEDLINE
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