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

Jarith L Ebenau, Sven J van der Lee, Marc Hulsman, Niccolò Tesi, Iris E Jansen, Inge M W Verberk, Mardou van Leeuwenstijn, Charlotte E Teunissen, Frederik Barkhof, Niels D Prins, Philip Scheltens, Henne Holstege, Bart N M van Berckel, Wiesje M van der Flier

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Article numbere12229
Pages (from-to)e12229
JournalAlzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
Volume13
Issue number1
DOIs
Publication statusPublished - 2021

Bibliographical note

© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.

Funding

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 , and , and edited a volume in the series (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 , and . 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 . All funding is paid to her institution. Alzheimer's Research & Therapy Neurology: Neuroimmunology & Neuroinflammation Medidact Neurology Neuromethods Radiology, Brain, Neuroradiology, Multiple Sclerosis Journal Neurology Alzheimer's Research & Therapy Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. The SCIENCe project is supported by research grants from Gieskes‐Strijbis fonds and stichting Dioraphte. Wiesje van der Flier holds the Pasman chair. PET scans were funded by research grants from AVID and Piramal Neuroimaging. Frederik Barkhof is supported by the NIHR biomedical research center at UCLH. Genotyping was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco‐fuND FP‐829‐029 (ZonMW projectnumber 733051061). Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. The SCIENCe project is supported by research grants from Gieskes-Strijbis fonds and stichting Dioraphte. Wiesje van der Flier holds the Pasman chair. PET scans were funded by research grants from AVID and Piramal Neuroimaging. Frederik Barkhof is supported by the NIHR biomedical research center at UCLH. Genotyping was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061).

FundersFunder number
ADxNeurosciences
AVID
Boehringer
Brainstorm Therapeutics
EADB
EU‐JPND
Edwin Bouw Fonds
Gieskes-Strijbis fonds and stichting Dioraphte
Gieskes‐Strijbis fonds and stichting Dioraphte
Health Holland
JPco-fuND FP-829-029
JPco‐fuND FP‐829‐029
Piramal Neuroimaging
Selfridges Group Foundation
Toyama Fujifilm
Alzheimer's Association
Alzheimer's Drug Discovery Foundation
Roche
EU Joint Programme – Neurodegenerative Disease Research
Avid Radiopharmaceuticals
National Institute for Health Research
European Commission
ZonMw733051061
Nederlandse Organisatie voor Wetenschappelijk OnderzoekEU‐FP7
Alzheimer Nederland
UCLH Biomedical Research Centre

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