Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits

Fahri Küçükali, Alexander Neumann, the EMIF-AD Study Group, for the Alzheimer's Disease Neuroimaging Initiative, Jasper Van Dongen, Tim De Pooter, Geert Joris, Peter De Rijk, Olena Ohlei, Valerija Dobricic, Isabelle Bos, Stephanie J.B. Vos, Sebastiaan Engelborghs, Ellen De Roeck, Rik Vandenberghe, Silvy Gabel, Karen Meersmans, Magda Tsolaki, Frans Verhey, Pablo Martinez-LageMikel Tainta, Giovanni Frisoni, Oliver Blin, Jill C. Richardson, Régis Bordet, Philip Scheltens, Julius Popp, Gwendoline Peyratout, Peter Johannsen, Lutz Frölich, Yvonne Freund-Levi, Johannes Streffer, Simon Lovestone, Cristina Legido-Quigley, Mara ten Kate, Frederik Barkhof, Henrik Zetterberg, Lars Bertram, Mojca Strazisar, Pieter Jelle Visser, Christine Van Broeckhoven, Kristel Sleegers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Downloads (Pure)


Introduction: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes. Methods: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808). Results: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively. Discussion: The identification of these novel gene–trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.

Original languageEnglish
JournalAlzheimer's and Dementia
Publication statusE-pub ahead of print - 4 Dec 2022

Bibliographical note

Funding Information:
EMIF: The present study was conducted as part of the European Medical Information Framework for Alzheimer's Disease (EMIF‐AD) project, which has received support from the Innovative Medicines Initiative Joint Undertaking under the European Medical Information Framework (EMIF) grant agreement no. 115372, the European Prevention of Alzheimer's Dementia (EPAD) grant no. 115736, and from the European Union's Horizon 2020 research and innovation programme under grant agreement no. 666992, resources of which are composed of financial contributions from the European Union's Seventh Framework Program (FP7/2007‐2013) and the European Federation of Pharmaceutical Industries and Association (EFPIA) companies' in‐kind contribution. The Development of Screening Guidelines and Criteria for Predementia Alzheimer's Disease (DESCRIPA) study was funded by the European Commission within the fifth framework program (QLRT‐2001‐2455). The Beta Amyloid Oligomers in Early Diagnosis of AD and as Marker for Treatment Response (EDAR) study was funded by the European Commission within the fifth framework program (contract no. 37670). The San Sebastian Gipuzkoa Alzheimer Project (GAP) study is partially funded by the Department of Health of the Basque Government (allocation The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant nos. 11020, 13007, and 15005). The Lausanne cohort was supported by grants from the Swiss National Research Foundation (SNF 320030_141179), Synapsis Foundation ‐ Alzheimer Research Switzerland (grant no. 2017‐PI01). F.K. is recipient of a PhD fellowship of the University of Antwerp Research Fund. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (no. 2018‐02532), the European Research Council (no. 681712), Swedish State Support for Clinical Research (no. ALFGBG‐720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (no. 201809‐2016862), the AD Strategic Fund and the Alzheimer's Association (nos. ADSF‐21‐831376‐C, ADSF‐21‐831381‐C, and ADSF‐21‐831377‐C), the Olav Thon Foundation, the Erling‐Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019‐0228), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at University College London. F.B. is supported by the National Institute for Health and Care Research (NIHR) biomedical research centre at University College London Hospitals (UCLH). This work was supported for Y.F‐L. by grants from the Petrus and Augusta Hedlunds Foundation, the Gun och Bertil Stohnes Foundation, the Loo and Hans Osterman Foundation, the Demensförbundet, Brain Foundation “Hjärnfonden” (grant FO2018‐0315), “Särfond 31 Forskning Senil demens,” Region Örebro län, “Stiftelsen for Gamla Tjänarinnor,” and Demensfonden, Stockholm and Nyckelfonden Region Örebro Län.

Publisher Copyright:
© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.


Dive into the research topics of 'Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits'. Together they form a unique fingerprint.

Cite this