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Aging and disease    2017, Vol. 8 Issue (2) : 215-227     DOI: 10.14336/AD.2016.0811
Original Article |
Serum Hepcidin Levels, Iron Dyshomeostasis and Cognitive Loss in Alzheimer’s Disease
Sternberg Zohara1,*, Hu Zihua2, Sternberg Daniel1, Waseh Shayan3, Quinn Joseph F.4, Wild Katharine4, Jeffrey Kaye4, Zhao Lin5, Garrick Michael5,6
1Department of Neurology, Stroke Center, Buffalo Medical Center, Buffalo, NY, USA.
2Center for Computational Research, New York State Center for Excellence in Bioinformatics and Life Sciences, University at Buffalo, Buffalo, NY, USA.
3Department of Biology, State University of New York at Buffalo, Buffalo, NY 14260 USA.
4Layton Aging & Alzheimer's Research Center, Oregon Health and Science University, Portland, Oregon, USA.
5Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY 14214 USA.
6Department of Pediatrics, State University of New York at Buffalo, Buffalo, NY 14214 USA.
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Abstract  

This pilot study examined the status of the master iron regulatory peptide, hepcidin, and peripheral related iron parameters in Alzheimer’s disease (AD) and mild cognitive impairment patients, and evaluated the relationship between iron dyshomeostasis and amyloid-beta (Aβ), cognitive assessment tests, neuroimaging and clinical data. Frozen serum samples from the Oregon Tissue Bank were used to measure serum levels of hepcidin, ferritin, Aβ40, Aβ42 using enzyme-linked immunosorbent assay. Serum transferrin levels were determined indirectly as total iron binding capacity, serum iron was measured and the percent saturation of transferrin calculated. The study variables were correlated with the patients’ existing cognitive assessment tests, neuroimaging, and clinical data. Hepcidin, and iron-related proteins tended to be higher in AD patients than controls, reaching statistical significance for ferritin, whereas Aβ40, Aβ42 serum levels tended to be lower. Patients with pure AD had three times higher serum hepcidin levels than controls; gender differences in hepcidin and iron-related proteins were observed. Patient stratification based on clinical dementia rating-sum of boxes revealed significantly higher levels of iron and iron-related proteins in AD patients in the upper 50% as compared to controls, suggesting that iron dyshomeostasis worsens as cognitive impairment increases. Unlike Aβ peptides, iron and iron-related proteins showed significant association with cognitive assessment tests, neuroimaging, and clinical data. Hepcidin and iron-related proteins comprise a group of serum biomarkers that relate to AD diagnosis and AD disease progression. Future studies should determine whether strategies targeted to diminishing hepcidin synthesis/secretion and improving iron homeostasis could have a beneficial impact on AD progression.

Keywords Alzheimer’s disease      Ferritin      Inflammation      Iron homeostasis      Mild cognitive impairment      Percent transferrin saturation      Serum biomarker     
Corresponding Authors: Sternberg Zohara   
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These authors contributed equally to this work

Issue Date: 01 April 2017
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Sternberg Zohara
Hu Zihua
Sternberg Daniel
Waseh Shayan
Quinn Joseph F.
Wild Katharine
Jeffrey Kaye
Zhao Lin
Garrick Michael
Cite this article:   
Sternberg Zohara,Hu Zihua,Sternberg Daniel, et al. Serum Hepcidin Levels, Iron Dyshomeostasis and Cognitive Loss in Alzheimer’s Disease[J]. Aging and disease, 2017, 8(2): 215-227.
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http://www.aginganddisease.org/EN/10.14336/AD.2016.0811     OR     http://www.aginganddisease.org/EN/Y2017/V8/I2/215
nAge (yrs)MMSECDRCDR-SOBAPOE4 (1 copy)P
Groups
AD (total)52 (M=37)70±718.42±6.21.085±0.66.456±3.040 (77%)
pure AD19 (M=10)69±716.82±6.31.13±0.696.46±2.514 (74%)
MCI9 (M=8)75±1129.09±1.50.13±0.20.1±0.22 (22%)<0.001
Controls24 (M=9)68±929.25±1.20.041±0.10.041±0.12 (8%)<0.001
Table 1  Population characteristics
Figure 1.  Distribution of hepcidin, iron-related parameters and Aβ stratified by AD versus controls and by gender (with totals). Box and whiskers plots compare serum levels of hepcidin (Hep) (A), ferritin (Ferr) (B), iron (Fe) (C), TIBC (D), percent transferrin saturation (E), Aβ40 (f), Aβ42 (g), and Aβ40/42 ratio (h).
Figure 2.  Distribution of hepcidin, iron-related parameters and Aβ stratified by AD versus MCI and controls. Box and whiskers plots compare serum levels of hepcidin (Hep) (a), ferritin (Ferr) (b), iron (Fe) (c), TIBC (d), percent transferrin saturation (e), Aβ40 (f), Aβ42 (g), and Aβ40/42 ratio (h).
Iron and Aβ status for AD versus controls, stratified by gender

VariableAD (M)Control (M)PAD (F)Control (F)PAD (T)P
Hepcidin (ngml)18.31±20.39.05±16.40.110.53±24.315±38.10.916.71±21.30.28
Ferritin (ng/ml)68.74±56.133.48±35.50.124.55±28.112.79±21.50.544.19±54.90.004
Serum Fe (μG/dL)92.59±69.662.5±100.80.567.7±67.551.8±86.50.383.27±68.40.32
TIBC (μG/dL)304.1±143.4257.25±135.30.6331.76±119.1297.35±66.40.1319.78±1370.25
% Saturation32.99±18.529.25±17.20.918.81±11.219.02±18.20.627.28±16.80.43
40 (pg/ml)289.08±133.6317.39±110.91326.34±125.6428.61±404.60.2297.62±131.50.14
42 (pg/ml)350.03±157.7461.31±138.70.1394.57±85.7356.14±132.40.3366.53±141.30.21
40/42 ratio0.83±0.270.64±0.150.20.87±0.341.01±1.30.30.86±0.30.71
Table 2  Iron and Aβ status for AD versus controls, stratified by gender
VariableCDR-SOBCDR-SOBCtrlsPPP
(0-6)(6.5-12)(0-6 vs.6.5-12)(0-6 vs. Ctrls)(6.5-12 vs.Ctrls)
Hepcidin (ngml)14.34±16.117.10±255.710.53±31.60.3960.5910.173
Ferritin (ng/ml)41.81±61.244.49±46.728.42±28.70.6220.0030.015
Fe (uG/dL)67.03±58.5100.55±74.155.47±89.90.0120.8280.032
TIBC (uG/dL)300.89±127.1353.21±139.9278.21±97.90.0530.9260.033
% Saturation25.24±15.132.87±18.120.32±17.70.1280.9910.134
40 (pg/ml)289.08±125.2309.02±131.8361.44±339.10.0750.0640.58
42 (pg/ml)360.81±139.5372.25±146.4418.87±137.60.8360.4120.288
40/42 Ratio0.83±0.20.87±0.30.80±1.10.1180.2670.548
Table 3  Iron and Aβ status for CDR-SOB (0-6) versus CDR-SOB (6.5-12) versus controls
Figure 3.  Correlations between measurements depend on diagnosis. For each panel, lines of regression indicate the existence or absence of a correlation and the shaded region shows the 95% confidence interval (CI) with data stratified by diagnosis of AD or control for hepcidin versus iron (A), hepcidin versus TIBC (B), hepcidin versus ferritin (C), and Aβ40 versus42 (D).
Figure 4.  Disease severity correlates with iron-related measurements in AD. Scatter plots with regression lines and shaded regions for the 95% confidence interval (CI) for % transferrin saturation versus CDRSOB (A), serum iron versus CDRSOB (B), hepcidin versus CDRSOB (C), % transferrin saturation versus ventricular CSF volume (D), serum iron versus ventricular CSF volume (E) and serum iron versus MMSE (F).
VariableMCIControlAD (T)P (MCI-Control)P (MCI-AD)
Hepcidin (ngml)15.1±40.510.53±31.616.71±21.30.3970.769
Ferritin (ng/ml)77.52±83.528.42±28.744.19±54.90.0250.363
Fe (uG/dL)38.86±39.855.47±89.983.27±68.40.2410.083
TIBC (uG/dL)263.13±50.7278.21±97.9319.78±1370.930.161
% Saturation16.75±11.620.32±17.727.28±16.80.640.227
40 (pg/ml)321.41±134.4361.44±339.1297.62±131.50.140.373
42 (pg/ml)462.60±154.5418.87±137.6366.53±141.30.330.091
40/42 Ratio0.69±0.20.80±1.10.86±0.30.1220.026
Table 4  Iron and Aβ status for MCI versus controls and MCI versus AD.
VariablesrP
Cognitive assessment tests

Serum Fe-CDRSOB0.3870.009
Serum Fe-CDR0.3610.015
Serum Fe-MMSE-0.2690.064
%Saturation-CDR0.3550.019
%Saturation-CDRSOB0.3190.042
Hepcidin-CDRSOB0.3290.03
Hepcidin-MMSE-0.2530.09
Aβ40-CDRSOB0.3210.04

Neuroimaging

Serum Fe-Vent. CSF Vol0.40.009
%Saturation-Vent. CSF Vol0.3830.015

Clinical

Hepcidin-Glucose0.4080.007
Hepcidin-Protein0.3730.01
%Saturation-MCV0.2950.051
APOE-Aβ40/42 ratio-0.3270.032
Table 5  Correlations to cognitive assessment tests, neuroimaging, and clinical data in AD patients.
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