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CDH6 and HAGH protein levels in plasma associate with Alzheimer’s disease in APOE ε4 carriers

Ahmad, Shahzad ; Milan, Marta del Campo ; Hansson, Oskar LU orcid ; Demirkan, Ayse ; Agustin, Ruiz ; Sáez, Maria E. ; Giagtzoglou, Nikolaos ; Cabrera-Socorro, Alfredo ; Bakker, Margot H.M. and Ramirez, Alfredo , et al. (2020) In Scientific Reports 10(1).
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 (Aβ) 42 levels in cerebrospinal fluid (CSF) in the Amsterdam Dementia Cohort (N = 441). Finally, we... (More)

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 (Aβ) 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 (β = 0.638, P = 3.33 × 10−4) and HAGH (β = 0.481, P = 7.20 × 10−4), were significantly elevated in APOE ε4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (β = 1.365, P = 3.97 × 10−3) and HAGH proteins (β = 0.506, P = 9.31 × 10−7) when comparing cases and controls in APOE ε4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE ε4 stratum (P < 1 × 10−3). The HAGH protein was not detected in CSF. GWAS of plasma CDH6 protein levels showed significant association with a cis-regulatory locus (rs111283466, P = 1.92 × 10−9). 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.

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type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
10
issue
1
article number
8233
publisher
Nature Publishing Group
external identifiers
  • scopus:85084962574
  • pmid:32427856
ISSN
2045-2322
DOI
10.1038/s41598-020-65038-5
language
English
LU publication?
yes
id
29ab12d8-2a18-4b64-9748-8ffe9edf165d
date added to LUP
2020-06-08 14:42:19
date last changed
2024-06-26 17:15:33
@article{29ab12d8-2a18-4b64-9748-8ffe9edf165d,
  abstract     = {{<p>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 (Aβ) 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 (β = 0.638, P = 3.33 × 10<sup>−4</sup>) and HAGH (β = 0.481, P = 7.20 × 10<sup>−4</sup>), were significantly elevated in APOE ε4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (β = 1.365, P = 3.97 × 10<sup>−3</sup>) and HAGH proteins (β = 0.506, P = 9.31 × 10<sup>−7</sup>) when comparing cases and controls in APOE ε4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE ε4 stratum (P &lt; 1 × 10<sup>−3</sup>). The HAGH protein was not detected in CSF. GWAS of plasma CDH6 protein levels showed significant association with a cis-regulatory locus (rs111283466, P = 1.92 × 10<sup>−9</sup>). 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.</p>}},
  author       = {{Ahmad, Shahzad and Milan, Marta del Campo and Hansson, Oskar and Demirkan, Ayse and Agustin, Ruiz and Sáez, Maria E. and Giagtzoglou, Nikolaos and Cabrera-Socorro, Alfredo and Bakker, Margot H.M. and Ramirez, Alfredo and Hankemeier, Thomas and Stomrud, Erik and Mattsson-Carlgren, Niklas and Scheltens, Philip and van der Flier, Wiesje M. and Ikram, M. Arfan and Malarstig, Anders and Teunissen, Charlotte E. and Amin, Najaf and van Duijn, Cornelia M.}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{CDH6 and HAGH protein levels in plasma associate with Alzheimer’s disease in APOE ε4 carriers}},
  url          = {{http://dx.doi.org/10.1038/s41598-020-65038-5}},
  doi          = {{10.1038/s41598-020-65038-5}},
  volume       = {{10}},
  year         = {{2020}},
}