Supplemental Digital Content 1 Supplemental methods The

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Supplemental Digital Content 1
Supplemental methods
The Alzheimer’s Disease Neuroimaging Initiative (ADNI) was launched in 2003 by the
National Institute on Aging (NIA), the National Institute of Biomedical Imaging and
Bioengineering (NIBIB), the Food and Drug Administration (FDA), private
pharmaceutical companies, and non-profit organizations as a $60 million, 5-year
public-private partnership. The primary goal of the ADNI has been to explore whether
serial magnetic resonance imaging (MRI), positron emission tomography (PET),
other biological markers, and clinical and neuropsychological data can be combined
to assess the progression of mild cognitive impairment (MCI) and early Alzheimer’s
disease (AD) dementia. The purpose of accurate markers for AD at an early clinical
stage is to stimulate the development of novel treatments, to monitor the
effectiveness of these strategies, and to reduce the duration and cost of clinical trials.
The Principal Investigator of this initiative is Michael W. Weiner, MD, VA Medical
Center and University of California San Francisco. The goal of the recruitment
process was to gather 800 adults aged 55 to 90 over 50 sites across the USA and
Canada for participation in the research; follow-up examinations were scheduled for
200 cognitively normal older individuals over three years; for 400 people with MCI
over three years; and for 200 people with early AD dementia over two years. Detailed
information on the ADNI can be found in previous publications and at www.adniinfo.org.
Supplemental table 1. 146 plasma biomarkers measured using the Luminex xMAP
platform (Luminex Corp. Austin, TX, USA) by Rules-Based Medicine (RBM Inc.
Austin, TX, USA).
#
Protein symbol
Protein name (unit)
1
A1Micro
Alpha-1-Microglobulin (µg/mL)
2
A2Macro
Alpha-2-Macroglobulin (mg/mL)
3
AACT
Alpha-1-Antichymotrypsin (µg/mL)
4
AAT
Alpha-1-Antitrypsin (mg/mL)
5
ACE
Angiotensin-Converting Enzyme (ng/mL)
6
Adiponectin
Adiponectin (µg/mL)
7
AFP
Alpha-Fetoprotein (ng/mL)
8
AGRP
Agouti-Related Protein (pg/mL)
9
ANG2
Angiopoietin-2 (ng/mL)
10
Angiotensinogen
Angiotensinogen (ng/mL)
11
ApoAI
Apolipoprotein A-I (mg/mL)
12
ApoAII
Apolipoprotein A-II (ng/ml)
13
ApoAIV
Apolipoprotein A-IV (µg/ml)
14
ApoB
Apolipoprotein B (µg/ml)
15
ApoCI
Apolipoprotein C-I (ng/mL)
16
ApoCIII
Apolipoprotein C-III (µg/mL)
17
ApoD
Apolipoprotein D (µg/mL)
18
ApoE
Apolipoprotein E (µg/mL)
19
ApoH
Apolipoprotein H (µg/mL)
20
AXL
AXL Receptor Tyrosine Kinase (ng/mL)
21
B2M
Beta-2-Microglobulin (µg/mL)
22
BDNF
Brain-Derived Neurotrophic Factor (ng/mL)
23
BLC
B Lymphocyte Chemoattractant (pg/mL)
24
BMP6
Bone Morphogenetic Protein 6 (ng/mL)
25
BNP
Brain Natriuretic Peptide (pg/mL)
26
BTC
Betacellulin (pg/mL)
27
C3
Complement C3 (mg/mL)
28
CA199
Cancer Antigen 19-9 (U/mL)
29
Calcitonin
Calcitonin (pg/mL)
30
CD40
CD 40 antigen (ng/mL)
31
CD40L
CD40 Ligand (ng/mL)
32
CD5L
CD5 Ligand (ng/mL)
33
CEA
Carcinoembryonic Antigen (ng/mL)
34
CgA
Chromogranin-A (ng/mL)
35
CKMB
Creatine Kinase-MB (CK-MB) (ng/mL)
36
CLU
Clusterin (ug/mL)
37
CNTF
Ciliary Neurotrophic Factor (pg/mL)
38
CFH
Complement Factor H (ug/mL)
39
Cortisol
Cortisol (ng/mL)
40
Cpeptide
C-peptide (ng/mL)
41
CRP
C-Reactive Protein (ug/mL)
42
CystatinC
Cystatin-C (ng/mL)
43
EGF
Epidermal Growth Factor (pg/mL)
44
EGFR
Epidermal Growth Factor Receptor (ng/mL)
45
EPGA
Epithelial-Derived Neutrophil-Activating (ng/mL)
46
Eotaxin1
Eotaxin-1 (pg/mL)
47
Eotaxin-3
Eotaxin-3 (pg/mL)
48
ESelectin
E-Selectin (ng/mL)
49
FABP
Fatty Acid-Binding Protein-heart (ng/mL)
50
FactorVII
Factor VII (ng/mL)
51
FAS
FASLG Receptor (ng/mL)
52
FasL
Fas Ligand (pg/mL)
53
FetuinA
Fetuin-A (µg/mL)
54
FGF4
Fibroblast Growth Factor 4) (pg/mL)
55
Fibrinogen
Fibrinogen (mg/mL)
56
FRTN
Ferritin (ng/mL)
57
FSH
Follicle-Stimulating Hormone (mIU/mL)
58
GH
Growth Hormone (ng/mL)
59
GROalph
Growth-Regulated alpha protein (pg/mL)
60
GSTalp
Glutathione S-Transferase alpha (ng/mL)
61
Haptoglobin
Haptoglobin (mg/mL)
62
HB
Heparin-Binding EGF-Like Growth Factor (pg/mL)
63
HCC4
Chemokine CC-4 (ng/mL)
64
HGF
Hepatocyte Growth Factor (ng/mL)
65
I3
T Lymphocyte-Secreted Protein I-309 (pg/mL)
66
ICAM
Intercellular Adhesion Molecule 1 (ng/mL)
67
IgA
Immunoglobulin A (mg/mL)
68
IgE
Immunoglobulin E (ng/mL)
69
IGF-BP
Insulin-like Growth Factor-Binding Protein (ng/mL)
70
IgM
Immunoglobulin M (mg/mL)
71
IL-13
Interleukin-13 (pg/mL)
72
IL-16
Interleukin-16 (pg/mL)
73
IL-18
Interleukin-18 (pg/mL)
74
IL-3
Interleukin-3 (IL-3) (ng/mL)
75
IL-6r
Interleukin-6 receptor (ng/mL)
76
IL-8
Interleukin-8 (pg/mL)
77
Insulin
Insulin (µlU/mL)
78
IP-10
Interferon gamma Induced Protein 10 (pg/ml)
79
KIM1
Kidney Injury Molecule-1 (KIM-1) (ng/ml)
80
Leptin
Leptin (ng/mL)
81
LH
Luteinizing Hormone (mIU/mL)
82
Lpa
Apolipoprotein(a) (ug/mL)
83
MCP1
Monocyte Chemotactic Protein 1 (pg/mL)
84
MCP2
Monocyte Chemotactic Protein 2 (pg/mL)
85
MCP3
Monocyte Chemotactic Protein 3 (pg/mL)
86
MCP4
Monocyte Chemotactic Protein 4 (pg/mL)
87
MCSF1
Macrophage Colony-Stimulating Factor 1 ( (ng/mL)
88
MDC
Macrophage-Derived Chemokine (pg/mL)
89
MMIF
Macrophage Migration Inhibitory Factor (ng/mL)
90
MI
Monokine Induced by Gamma Interferon (pg/ml)
91
MIP1alpha
Macrophage Inflammatory Protein-1 alpha (pg/mL)
92
MIP1beta
Macrophage Inflammatory Protein-1 beta (pg/mL)
93
MIP3alpha
Macrophage Inflammatory Protein-3 alpha (pg/ml)
94
MMP1
Matrix Metalloproteinase-1 (ng/ml)
95
MMP10
Matrix Metalloproteinase-10 (MMP-10) (ng/ml)
96
MMP2
Matrix Metalloproteinase-2 (ng/mL)
97
MMP7
Matrix Metalloproteinase-7 (ng/mL)
98
MMP9
Matrix Metalloproteinase-9 (ng/mL)
99
MMP9t
Matrix Metalloproteinase-9-total (ng/ml)
100
MPIF
Myeloid Progenitor Inhibitory Factor 1 (ng/mL)
101
MPO
Myeloperoxidase (ng/mL)
102
Myoglobin
Myoglobin (ng/mL)
103
NGAL
Neutrophil Gelatinase-Associated Lipocal (ng/ml)
104
NrCAM
Neuronal Cell Adhesion Molecule (ng/mL)
105
Osteopontin
Osteopontin (ng/ml)
106
PAI1
Plasminogen Activator Inhibitor 1 (ng/mL)
107
PAP
Prostatic Acid Phosphatase (PAP) (ng/mL)
108
PAPPAP
Pregnancy-Associated Plasma Protein A (P (mIU/mL)
109
PARC
Pulmonary and Activation-Regulated Chemo (ng/mL)
110
PDGF-BB
Platelet-Derived Growth Factor BB (pg/mL)
111
PLGF
Placenta Growth Factor (pg/mL)
112
PPP
Pancreatic Polypeptide (pg/mL)
113
PRL
Prolactin (ng/mL)
114
ProinsulinI
Proinsulin-Intact (pM)
115
ProinsulinT
Proinsulin-Total (pM)
116
PYY
Peptide YY (pg/mL)
117
RAGE
Receptor for advanced glycosylation end (ng/mL)
118
Tcee
T-Cell-Specific Protein RANTES (ng/mL)
119
Resistin
Resistin (ng/mL)
120
SAP
Serum Amyloid P-Component (ug/mL)
121
SCF
Stem Cell Factor (pg/mL)
122
SGOT
Serum Glutamic Oxaloacetic Transaminase (ug/mL)
123
SHBG
Sex Hormone-Binding Globulin (SHBG) (nmol/L)
124
SOD1
Superoxide Dismutase 1- Soluble (SOD-1) (ng/mL)
125
Sortilin
Sortilin (ng/mL)
126
TBG
Thyroxine-Binding Globulin (TBG) (ug/mL)
127
TECK
Thymus-Expressed Chemokine (TECK) (ng/mL)
128
TestosteroneTotal
Testosterone- Total (ng/mL)
129
TFF3
Trefoil Factor 3 (TFF3) (ug/ml)
130
THP
Tamm-Horsfall Urinary Glycoprotein (THP) (ug/ml)
131
Thrombospondin1
Thrombospondin-1 (ng/mL)
132
TIM1
Tissue Inhibitor of Metalloproteinases 1 (ng/mL)
133
TM
Thrombomodulin (TM) (ng/mL)
134
TNC
Tenascin-C (TN-C) (ng/mL)
135
TNFalpha
Tumor Necrosis Factor alpha (pg/mL)
136
TNFrL2
Tumor Necrosis Factor Receptor-Like 2 (T (ng/mL)
137
Thrombopoietin
Thrombopoietin (ng/mL)
138
TNF
TNF-Related Apoptosis-Inducing Ligand Re (ng/mL)
139
Serotransferrin
Serotransferrin (mg/dl)
140
TSH
Thyroid-Stimulating Hormone (µIU/mL)
141
TTR
Transthyretin (mg/dL)
142
VCAM1
Vascular Cell Adhesion Molecule-1 (ng/mL)
143
VEGF
Vascular Endothelial Growth Factor (pg/mL)
144
Vitronectin
Vitronectin (µg/mL)
145
VKDPS
Vitamin K-Dependent Protein S (µg/mL)
146
vWF
von Willebrand Factor (µg/mL)
Supplemental table 2. Network identified from IPA for a migration signature and
plasma biomarker panel for Alzheimer’s disease
Network #
Gene symbol (name) in
Ingenuity Network*
Functions of the Network
Score**
AMBP (alpha-1-microglobulin)
ApoE (apolipoprotein E)
1
NPPB (brain natriuretic peptide)
 Cellular Death
 Lipid Metabolism
 Molecular transport
17
IL16 (Interleukin-16)
* Genes were part of a single functional genomic pathway identified by IPA. ** The
score indicates the likelihood of the genes in a network from the Ingenuity knowledge
base being found together due to random chance. A score > 3 is considered
significant.
Supplemental table 3. 79 plasma biomarkers published in 13 previous proteomic
studies in Alzheimer’s disease
Protein symbol
Protein name
References
1
AAT
Alpha-1-Antitrypsin
(Liao et al., 2007)
2
ACT
Alpha-1-Antichymotrypsin
(Engelhart et al., 2004)
3
Adiponectin
Adiponectin
(Britschgi et al., 2011)
Serum albumin precursor
(Hye et al., 2006)
a
4
ALB
5
Apo E
Apolipoprotein E
(Akuffo et al., 2008)
6
Apo J a
Apolipoprotein J
(Liao et al., 2007)
7
ApoCIII
Apolipoprotein C-III
(Britschgi et al., 2011)
8
B2M
Beta-2-Microglobulin
(Britschgi et al., 2011)
9
C1-INH a
Complement C1 Inhibitor
(Akuffo et al., 2008)
10
C3
Complement Component 3
(Thambisetty et al., 2011)
11
C3a
Complement C3a
(Thambisetty et al., 2011)
12
C4 precursor
Complement C4 precursor
(Hye et al., 2006)
13
CCL2/MCP1
Monocyte Chemotactic Protein 1
(Britschgi et al., 2011)
14
CCL7/ MCP-3
Monocyte Chemotactic Protein 3
(Ray et al., 2007)
15
CD40 Ligand
(Britschgi et al., 2011)
CD5 Antigen-Like Precursor
(Hye et al., 2006)
17
CD40L
CD5 antigen-like
precursor a
CF-I a
Complement Factor-I
(Thambisetty et al., 2011)
18
CK-MB
Creatine Kinase-MB
(Britschgi et al., 2011)
19
Cortisol
Cortisol
(Laske et al., 2011)
20
CP a
Ceruloplasmin Precursor
(Hye et al., 2006)
21
CRP
C-Reactive Protein
(Engelhart et al., 2004)
22
DBP a
Vitamin D-Binding Protein
(Liao et al., 2007)
23
Desmoplakin a
Desmoplakin
(Hye et al., 2006)
24
Fibrinogen
Fibrinogen
(Thambisetty et al., 2011)
Galectin-7
(Hye et al., 2006)
16
a
a
25
Galectin-7
26
GH
Growth Hormone
(Britschgi et al., 2011)
27
Histone H2B.a/g/h/k/l a
Histone H2B.a/g/h/k/l
(Hye et al., 2006)
28
IgA
Immunoglobulin A
(Britschgi et al., 2011)
29
IGFBP-2
Insulin-Like Growth Factor-Binding Protein 2
(Rocha de Paula et al., 2011)
30
IGFBP-6
Insulin-Like Growth Factor-Binding Protein 6
(Ray et al., 2007)
31
IGHA1 a
Ig alpha-1 chain C region
(Hye et al., 2006)
32
IGHG1 a
Ig gamma-1 chain C region
(Hye et al., 2006)
33
IGKC a
Ig kappa chain C region
(Hye et al., 2006)
34
IGKV-I a
Ig kappa chain V-I region Lay
(Hye et al., 2006)
35
IGKV-II a
Ig kappa chain V-II region
(Hye et al., 2006)
36
IGKV-IV a
Ig kappa chain V-IV region Len
(Hye et al., 2006)
37
IGLC a
Ig lambda chain C regions
(Hye et al., 2006)
38
IGLV-II a
Ig lambda chain V-II region TRO
(Hye et al., 2006)
39
IGLV-III a
Ig lambda chain V-III region LOI
(Hye et al., 2006)
Ig mu chain C region
(Hye et al., 2006)
a
40
IGMC
41
IL-12p70 a
Interleukin-12p70
(Britschgi et al., 2011)
42
IL-18
Interleukin-18
(Britschgi et al., 2011)
43
IL-1a a
Interleukin-1 alpha
(Ray et al., 2007)
44
IL-1b a
Interleukin-1 beta
(Zuliani et al., 2008)
45
IL-4 a
Interleukin-4
(Britschgi et al., 2011)
46
IL-6 a
Interleukin-6
(Engelhart et al., 2004)
47
insulin
Insulin
(Britschgi et al., 2011)
48
NT-3 a
Neurotrophin-3
(Rocha de Paula et al., 2011)
49
OLAB a
Oxidized LDL Antibodies
(Laske et al., 2011)
50
PAI1
Plasminogen Activator Inhibitor 1
(Britschgi et al., 2011)
51
PKA-C a
Protein kinase A-C
(Liao et al., 2007)
52
RAGE
Receptor for Advanced Glycosylation End
(Britschgi et al., 2011)
53
SAP
Serum amyloid P-component Precursor
(Hye et al., 2006)
54
TBG
Thyroxine-Binding Globulin
(Britschgi et al., 2011)
55
TF
Tissue Factor
(Britschgi et al., 2011)
56
TIMP1
Tissue Inhibitor of Metalloproteinases 1
(Britschgi et al., 2011)
57
TNF RII a
Tumor Necrosis Factor receptor II
(Britschgi et al., 2011)
58
TNFb a
(Britschgi et al., 2011)
59
TRAIL-R4 a
60
VCAM-1
Tumor Necrosis Factor beta
TNF-Related Apoptosis-Inducing Ligand
Receptor 4
Vascular Cell Adhesion Molecule-1
61
VEGF-B
Vascular Endothelial Growth Factor
(Rocha de Paula et al., 2011)
62
vWF
von Willebrand Factor
(Laske et al., 2011)
63
A2M
Alpha-2-Macroglobulin
64
ANG-2
Angiopoietin-2
(Akuffo et al., 2008; Hye et al., 2006;
Thambisetty et al., 2008; Thambisetty et
al., 2011)
(Ray et al., 2007; Rocha de Paula et al.,
2011; Soares et al., 2009)
65
CCL15/MIP-1d a
Macrophage Inflammatory Protein-1 delta
(Marksteiner et al., 2011; Ray et al.,
2007; Rocha de Paula et al., 2011)
66
CCL18/PARC
Pulmonary and Activation-Regulated Chemo
(Ray et al., 2007; Soares et al., 2009)
67
CCL5/RANTES
T-Cell-Specific Protein RANTES
(Marksteiner et al., 2011; Ray et al.,
2007; Soares et al., 2009)
68
CFH
Complement Factor H
(Akuffo et al., 2008; Hye et al., 2006;
Thambisetty et al., 2008)
69
CXCL8/IL-8
Interleukin-8
(Ray et al., 2007; Soares et al., 2009)
70
EGF
Epidermal Growth Factor
(Ray et al., 2007; Soares et al., 2009)
71
G-CSF a
Granulocyte Colony-Stimulating Factor
72
GDNF a
Glial Cell Line–Derived Neurotrophic Factor
73
ICAM-1
74
IHRP a
75
IL-11 a
Intercellular Adhesion Molecule 1
interalpha-trypsin inhibitor family heavy
chain-related protein
Interleukin-11
(Ray et al., 2007)
(Zuliani et al., 2008)
(Britschgi et al., 2011; Marksteiner et al.,
2011; Ray et al., 2007; Rocha de Paula
et al., 2011)
(Marksteiner et al., 2011; Ray et al.,
2007)
(Ray et al., 2007; Soares et al., 2009)
(Hye et al., 2006; Liao et al., 2007)
(Ray et al., 2007; Rocha de Paula et al.,
2011)
76
IL-3
Interleukin-3
(Britschgi et al., 2011; Ray et al., 2007;
Soares et al., 2009)
77
M-CSF a
Macrophage Colony-Stimulating Factor
(Britschgi et al., 2011; Ray et al., 2007;
Soares et al., 2009)
78
PDGF
Platelet-Derived Growth Factor
79
TNFa
Tumor Necrosis Factor alpha
(Ray et al., 2007; Rocha de Paula et al.,
2011; Soares et al., 2009)
(Marksteiner et al., 2011; Ray et al.,
2007; Soares et al., 2009; Zuliani et al.,
2008)
No. 1—62: biomarkers identified in a single proteomic study; No. 63—79: biomarkers
identified in at least two independent proteomic studies. a biomarkers not tested in the
ADNI plasma biomarker core. AD: Alzheimer’s disease; ADNI: Alzheimer's Disease
Neuroimaging Initiative
Supplemental figure 1. The Putative gene network derived from IPA software that
shows a schematic flow diagram of a functional genomic pathway of 4 selected
plasma biomarkers with amyloid precursor protein and tau
IPA scans the set of input genes to identify networks by using Ingenuity Pathways
Knowledge Base. Networks are displayed graphically as genes/gene products
(“nodes”) with the biological relationships between the nodes (“edges”) identified.
Edges are displayed with labels that describe the nature of the relationship between
the nodes. The lines between genes represent known interactions, with solid lines
representing direct interactions and with dashed lines representing indirect or
hypothetical interactions. Color highlighting (red) indicates pathway-associated genes
discovered by this study and non-highlighted genes are those identified by IPA.
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