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. 2020 May 19;10(1):8233.
doi: 10.1038/s41598-020-65038-5.

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

Shahzad Ahmad  1 , Marta Del Campo Milan  2 , Oskar Hansson  3   4 , Ayse Demirkan  5 , Ruiz Agustin  6   7 , Maria E Sáez  8 , Nikolaos Giagtzoglou  9 , Alfredo Cabrera-Socorro  10 , Margot H M Bakker  11 , Alfredo Ramirez  12   13   14 , Thomas Hankemeier  15 , Erik Stomrud  3   4 , Niklas Mattsson-Carlgren  3   4 , Philip Scheltens  16 , Wiesje M van der Flier  16 , M Arfan Ikram  5 , Anders Malarstig  17   18 , Charlotte E Teunissen  2 , Najaf Amin  5 , Cornelia M van Duijn  19   20
Affiliations

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

Shahzad Ahmad et al. Sci Rep. .

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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Conflict of interest statement

S.A., M.C.M., A.D., R.A., M.E.S., A.R., T.H., E.S., N.M., P.S., M.A.I., N.A., C.M.D. declare no competing interests. O.H. has acquired research support (for the institution) from Roche, Pfizer, GE Healthcare, Biogen, AVID Radiopharmaceuticals and Euroimmun. In the past 2 years, O.H. has received consultancy/speaker fees (paid to the institution) from Biogen and Roche. Dr. Nikolaos Giagtzoglou was an employee at Biogen Idec, USA. Dr. Alfredo Cabrera-Socorro is an employee of Janssen Pharmaceutical NV, Turnhoutseweg 30, 2340 Beerse, Belgium. Dr. Margot H.M. Bakker is a full time employee of AbbVie GmbH & Co KG and owns AbbVie stock. AbbVie contributed to the study design, research, and interpretation of data, reviewing, and approving the publication. Prof. dr. Teunissen has functioned in advisory boards of Roche, received non-financial support in the form of research consumables from ADxNeurosciences and Euroimmun, performed contract research or received grants from Probiodrug, Biogen, Esai, Toyama, Janssen prevention center, Boehringer, AxonNeurosciences, EIP farma, PeopleBio, Roche.Research programs of Prof. dr. Wiesje van der Flier have been funded by ZonMW, NWO, EU-FP7, Alzheimer Nederland, CardioVascular Onderzoek Nederland, stichting Dioraphte, Gieskes-Strijbis fonds, Pasman stichting, Biogen MA Inc, Boehringer Ingelheim, Piramal Neuroimaging, Roche BV, Janssen Stellar, Combinostics. WF holds the Pasman chair. WF has performed contract research for Biogen MA Inc and Boehringer Ingelheim. WF has been an invited speaker at Boehringer Ingelheim and Biogen MA Inc. All funding is paid to her institution.

Figures

Figure 1
Figure 1
Volcano plots representing the association of plasma protein levels with Alzheimer’s disease (AD) in (a) overall analysis; (b) APOE4 stratum; (c) APOE33 stratum and (d) APOE2 stratum. Each dot represents a protein with regression coefficient (β) of association plotted on x-axis and -log10 of P-values on y-axis. Proteins showing nominal association (P-value < 0.05) are annotated in overall and stratified analysis. Light blue color of dot indicates decreased protein levels with β −0.0 to −0.184 and dark blue to indicate with β < −0.184 while pink color indicates increased protein levels with β ranging from 0.0 to 0.184 and red color shows β > 0.184. Black dots are used for proteins which pass the multiple testing (false discovery rate <0.05).
Figure 2
Figure 2
Venn diagram showing the overlap of proteins identified in the association analysis results of overall and APOE stratified discovery analysis.
Figure 3
Figure 3
Correlation plot between cerebrospinal fluid (CSF) levels of CDH6 with Aβ−42, p-tau and t-tau.
Figure 4
Figure 4
Flowchart of the analyses. Rotterdam Study was used as discovery cohort in plasma-based proteomics analysis. Altered proteins in plasma analysis were replicated in the BioFINDER study and further validated in Amsterdam Dementia Cohort participants. Abbreviations; AD: Alzheimer’s disease; APOE: apolipoprotein E; GWAS: genome-wide association study; CSF: cerebrospinal fluid.
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