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

Abstract

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.

• Authors: 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, Alzheimer's Disease Neuroimaging Initiative (ADNI), Alberto Lleó, Daniel Alcolea, Julius 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, Lars Bertram
• Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association (Alzheimers Dement) Vol. 17 Issue 10 Pg. 1628-1640 (10 2021) ISSN: 1552-5279 [Electronic] United States
• PMID: 33991015 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

Chemical References

• Biomarkers
• CHI3L1 protein, human
• Chitinase-3-Like Protein 1
• Membrane Proteins
• Nerve Tissue Proteins
• Neurofilament Proteins
• TMEM106B protein, human
• neurofilament protein L
• Neurogranin

Topics

• Aged
• Alzheimer Disease (genetics)
• Biomarkers (cerebrospinal fluid)
• Chitinase-3-Like Protein 1 (genetics)
• Female
• Genome-Wide Association Study
• Humans
• Male
• Membrane Proteins (genetics)
• Nerve Tissue Proteins (genetics)
• Neurofilament Proteins (genetics)
• Neurogranin (cerebrospinal fluid)