TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels

Shengjun Hong, Valerija Dobricic, Olena Ohlei, Isabelle Bos, Stephanie J. B. Vos, Dmitry Prokopenko, Betty M. Tijms, Ulf Andreasson, Kaj Blennow, Rik Vandenberghe, Silvy Gabel, Philip Scheltens, Charlotte E. Teunissen, Sebastiaan Engelborghs, Giovanni Frisoni, Olivier Blin, Jill C. Richardson, Regis Bordet, Alberto Lleó, Daniel AlcoleaJulius Popp, Christopher Clark, Gwendoline Peyratout, Pablo Martinez-Lage, Mikel Tainta, Richard J. B. Dobson, Cristina Legido-Quigley, Kristel Sleegers, Christine van Broeckhoven, Rudolph E. Tanzi, Mara ten Kate, Michael Wittig, Andre Franke, Christina M. Lill, Frederik Barkhof, Simon Lovestone, Johannes Streffer, Henrik Zetterberg, Pieter Jelle Visser, Alzheimer's Disease Neuroimaging Initiative (ADNI), Lars Bertram*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Introduction: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Methods: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. Results: We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. Discussion: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
Original languageEnglish
Pages (from-to)1628-1640
Number of pages13
JournalAlzheimer's and Dementia
Issue number10
Early online date2021
Publication statusPublished - Oct 2021

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