Universität zu Köln

Ahmad, Shahzad ORCID: 0000-0002-8658-3790, Milan, Marta del Campo, Hansson, Oskar ORCID: 0000-0001-8467-7286, Demirkan, Ayse, Agustin, Ruiz, Saez, Maria E., Giagtzoglou, Nikolaos, Cabrera-Socorro, Alfredo, Bakker, Margot H. M., Ramirez, Alfredo ORCID: 0000-0003-4991-763X, Hankemeier, Thomas, Stomrud, Erik, Mattsson-Carlgren, Niklas, Scheltens, Philip, van der Flier, Wiesje M., Ikram, M. Arfan, Malarstig, Anders, Teunissen, Charlotte E., Amin, Najaf and van Duijn, Cornelia M. (2020). CDH6 and HAGH protein levels in plasma associate with Alzheimer's disease in APOE epsilon 4 carriers. Sci Rep, 10 (1). LONDON: NATURE PUBLISHING GROUP. ISSN 2045-2322

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Abstract

Many Alzheimer's disease (AD) genes including Apolipoprotein E (APOE) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in plasma from 316 participants of the Rotterdam Study (incident AD=161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE. Findings from the Rotterdam study were replicated in 186 AD patients of the BioFINDER study. We further evaluated the correlation of these protein biomarkers with total tau (t-tau), phosphorylated tau (p-tau) and amyloid-beta (A beta) 42 levels in cerebrospinal fluid (CSF) in the Amsterdam Dementia Cohort (N=441). Finally, we conducted a genome-wide association study (GWAS) to identify the genetic variants determining the blood levels of AD-associated proteins. Plasma levels of the proteins, CDH6 (beta =0.638, P=3.33x10(-4)) and HAGH (beta =0.481, P=7.20x10(-4)), were significantly elevated in APOE epsilon 4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (beta =1.365, P=3.97x10(-3)) and HAGH proteins (beta =0.506, P=9.31x10(-7)) when comparing cases and controls in APOE epsilon 4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE epsilon 4 stratum (P<1x10(-3)). The HAGH protein was not detected in CSF. GWAS of plasma CDH6 protein levels showed significant association with a cis-regulatory locus (rs111283466, P=1.92x10(-9)). CDH6 protein is implicated in cell adhesion and synaptogenesis while HAGH protein is related to the oxidative stress pathway. Our findings suggest that these pathways may be altered during presymptomatic AD and that CDH6 and HAGH may be new blood-based biomarkers.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ahmad, Shahzad UNSPECIFIED orcid.org/0000-0002-8658-3790 UNSPECIFIED Milan, Marta del Campo UNSPECIFIED UNSPECIFIED UNSPECIFIED Hansson, Oskar UNSPECIFIED orcid.org/0000-0001-8467-7286 UNSPECIFIED Demirkan, Ayse UNSPECIFIED UNSPECIFIED UNSPECIFIED Agustin, Ruiz UNSPECIFIED UNSPECIFIED UNSPECIFIED Saez, Maria E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Giagtzoglou, Nikolaos UNSPECIFIED UNSPECIFIED UNSPECIFIED Cabrera-Socorro, Alfredo UNSPECIFIED UNSPECIFIED UNSPECIFIED Bakker, Margot H. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ramirez, Alfredo UNSPECIFIED orcid.org/0000-0003-4991-763X UNSPECIFIED Hankemeier, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Stomrud, Erik UNSPECIFIED UNSPECIFIED UNSPECIFIED Mattsson-Carlgren, Niklas UNSPECIFIED UNSPECIFIED UNSPECIFIED Scheltens, Philip UNSPECIFIED UNSPECIFIED UNSPECIFIED van der Flier, Wiesje M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ikram, M. Arfan UNSPECIFIED UNSPECIFIED UNSPECIFIED Malarstig, Anders UNSPECIFIED UNSPECIFIED UNSPECIFIED Teunissen, Charlotte E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Amin, Najaf UNSPECIFIED UNSPECIFIED UNSPECIFIED van Duijn, Cornelia M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-333373
DOI:	10.1038/s41598-020-65038-5
Journal or Publication Title:	Sci Rep
Volume:	10
Number:	1
Date:	2020
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2045-2322
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MILD COGNITIVE IMPAIRMENT; APOLIPOPROTEIN-E GENOTYPE; A-BETA; N-CADHERIN; CEREBROSPINAL-FLUID; SYNAPTIC LOCALIZATION; OXIDATIVE STRESS; MENTAL STATE; GLYOXALASE-I; RISK LOCI Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33337