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Cited by 31Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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

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Ahmad, Shahzad, Milan, Marta del Campo, Hansson, Oskar, Demirkan, Ayse, Agustin, Ruiz, Sáez, Maria E., Giagtzoglou, Nikolaos, Cabrera-Socorro, Alfredo +12 more·2020·Scientific Reports
DOI 10.1038/s41598-020-65038-5PMC PMC7237496
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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 (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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  • APOE isoforms differentially modulate components of cadherin-catenin complexes.

    “Cadherin signaling has also been linked to synaptic adhesion stability and neurodegeneration (Ando et al., 2011; Arikkath and Reichardt, 2008; Laszlo and Lele, 2022; Mysore et al., 2008), and APOE isoforms differentially modulate components of cadherin–catenin complexes (Ahmad et al., 2020; Zhang et al., 2024).”

    From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Ahmad et al., 2020

    The Results (‘Association of proteins with APOE’; page unavailable) report different plasma levels of CDH6, a cadherin, across APOE genotype groups. The paper does not show that APOE isoforms modulate cadherin–catenin complexes or their components beyond CDH6, and the observed association does not establish modulation. (LLM, conf=0.87)

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Authors
Ahmad, S., Milan, M. D. C., Hansson, O., Demirkan, A., Agustin, R., Sáez, M. E., Giagtzoglou, N., Cabrera-Socorro, A., Bakker, M. H. M., Ramirez, A., Hankemeier, T., Stomrud, E., Mattsson-Carlgren, N., Scheltens, P., van der Flier, W. M., Ikram, M. A., Malarstig, A., Teunissen, C. E., Amin, N., & van Duijn, C. M.
Affiliations
  • Erasmus MC (NL)
  • Lund University (SE)
  • AbbVie (Germany) (DE)
  • Leiden University (NL)
  • Amsterdam Neuroscience (NL)
Corresponding author
Ahmad, Shahzad
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2020-05-19
Volume
10
Issue
1
Pages
8233-8233
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-020-65038-5
PMC
PMC7237496
OpenAlex
W3026116304
Cited by
31
References
16
Citations by year
2026: 4 · 2025: 7 · 2024: 3 · 2023: 5 · 2022: 8 · 2021: 3 · 2020: 1
FWCI
3.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, cc-by)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by)
  • Leiden Repository (Leiden University) (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • Lund University Publications (Lund University) (submittedVersion)
  • DZNE Pub (submittedVersion, cc-by)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • Weston Brain Institute
  • European Federation of Pharmaceutical Industries and Associations (115975)
  • European Commission (HORIZON2020, 115975, 014-93-015)
  • ZonMw (733051021, 050-060-810)
  • Erasmus Medisch Centrum (050-060-810, 014-93-015)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (050.060.810, 014-93-015, 911-03-012, 175.010.200, 175.010.2005.011)
  • Stichting Dioraphte
  • Innovative Medicines Initiative (115975)
  • Alzheimer Nederland
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, CDH6, APOE ε4 carriers, plasma biomarkers, blood-based biomarkers, neuroproteins, total tau, phosphorylated tau, amyloid-beta 42, cerebrospinal fluid, preclinical Alzheimer's disease, oxidative stress, cell adhesion, synaptogenesis, Rotterdam Study
MeSH terms
Hydroxyacylglutathione Hydrolase, Alzheimer Disease, Genetic Carrier Screening, Humans, Thiolester Hydrolases, Biomarkers, Cadherins, Apolipoprotein E4

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