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

Fahri Küçükali, Alexander Neumann, 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-Lage, Mikel Tainta, Giovanni FrisoniOliver 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*, Alzheimer's Disease Neuroimaging Initiative (ADNI)

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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
Number of pages15
JournalAlzheimer's & Dementia
Publication statusE-pub ahead of print - 4 Dec 2022

Cite this