Table 2.
Studies of proteins as potential biomarkers for AD and PD.
| Disease | Sample | Participants (n) | Biomarker and Results | Analytical Method | Refs. |
|---|---|---|---|---|---|
| AD | Serum | AD (43), HC (43) | Proteomics: 61 peptides differentially expressed, 9 of them derived from Pregnancy zone protein (PZP). Increased levels of PZP were found in presymptomatic AD compared to HC. | Untargeted (LC-MS) | Ijsselstijn, 2011 [218] |
| AD (15), MCI (15), HC (15) | 195 proteins: Some identified proteins were associated with AD-related plaque particle formation. | Untargeted (Flow cytometer- MS) | Madasamy, 2015 [185] | ||
| AD (58), HC (55) Confirmatory study 68 AD (68), HC (57) |
Proteomics: A peptide, 2 phosphatidylcholine and a glycerophosphatidylcholine were confirmed as potential biomarkers for AD diagnosis. | Untargeted (Capillary liquid chromatography-MS) | Shah, 2016 [217] | ||
| AD (15), HC (15) | Proteomics: Zinc-alpha-2-glycoprotein, fibulin-1 (FBLN1), platelet basic protein, thrombospondin-1, S100 calcium-binding protein A8, and S100 calcium-binding protein A9 showed different levels between AD patients and HC. | Untargeted (iTRAQlabeling and high-pH RPLC fractionation NanoLC-MS/MS) | Shen, 2017 [216] | ||
| DLB (30), AD (30), HC (28) | 146 peptides: A model including 4 peptides could discriminate between DLB group from the non-DLB (AD and HC) with a sensitivity of 93.3% and specificity of 87.9%. | Untargeted (HPLC-matrix assisted laser desorption/ionization time-of-flight mass spectrometer) | Suzuki, 2015 [215] | ||
| High neocortical amyloid-β burden (NAB) (107), Low NAB (91) | Proteomics: Pancreatic polypeptide and IgM showed a significant association with NAB (Neocortical Amyloid-β Burden). | Untargeted (SOMAscan) | Voyle, 2015 [158] | ||
| AD (45), HC (20) | Proteomics: 6 proteins differentially expressed: actin, apolipoprotein A-IV (Apo A-IV), inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4), alpha-1-antitrypsin (AAT), antithrombin-III (AT-III) and activity-dependent neuroprotector homeobox protein (ADNP) | Untargeted (Two-dimensional gel electrophoresis, nano-HPLC-ESI-MS/MS, ELISA) | Yang, 2012 [179] | ||
| 6 sMCI (6), MCI-AD (6), AD (6), HC (6) | Proteomics: Complement C3 and alpha-2-macroglobulin were potential biomarkers for AD but not ready to be used in clinical practise. | Untargeted (LC-MS/MS, ELISA) | Zabel, 2012 [139] | ||
| Longitudinal, within-person analysis of serum NfL dynamics (196) preclinical AD | Neurofilament Light (NfL) has potential utility as a clinically useful biomarker. | Targeted (Array immunoassay technology) | Preische 2019 [219] | ||
| Pre-MCI (11), AD (4), HC (2) | Oligomeric proteins and variants are good AD biomarkers since early stages and they could serve as progression biomarkers | Targeted (Phage capture ELISA system) | Williams, 2017 [138] | ||
| AD (26), HC (24) | sAβPPα did not show differences between groups | Targeted (ELISA) | Taverna, 2013 [221] | ||
| AD (284), MCI (225), HC (557) | CRP Lower levels of CRP in AD compared to MCI and HC and reduced of this protein levels were found in MCI compared to HC. |
Targeted (multiplexedimmunoassay) | O’Bryant, 2013 [222] | ||
| Probable AD (192), HC (174) | Lower levels of CRP in AD than HC. | Targeted (multiplexed immunoassay) | O’Bryant, 2010 [180] | ||
| Probable AD (12), MCI (18), HC (13) | Leptin, hsCRP, IL-6 and TNF-α levels. TNF-α is associated with cognitive and functional decline at early clinical stages of dementia. |
Targeted (Leptin, IL-6 and TNF-a (ELISA), hsCRP (immunoturbidimetric method)) | Magalhães, 2018 [225] | ||
| AD (28), MCI (30), HC (77) | IL-18 and T-lymphocyte-secreted protein I-309 levels were different between groups. | Targeted (NA) | Villareal, 2016 [223] | ||
| Memantine-sensitive AD (90), memantine-insensitive AD (87) | A logistic regression model based on VEGF, BDNF, IL-6 and IL-1βfor diagnosing and choosing the best course of treatment for moderate AD | Targeted (ELISA) | Wei, 2018 [224] | ||
| AD (100), MCI (45), HC (100) | beta2-microglobulin could play a role in AD | Targeted (Solid-phase, two sites chemiluminescent immunometric assay on Immulite 2000 Automatic analyzer) | Dominici, 2018 [184] | ||
| AD (20), ALS (12), MS (42), tick-borne encephalitis (TBE) (12), HC (20). | Higher concentrations of free γc-globulin in patients suffering from neurodegenerative diseases | Targeted (ELISA) | Kułakowska, 2018 [162] | ||
| Disease | Sample | Participants (n) | Biomarker and Results | Analytical Method | Refs. |
| AD | Serum | AD (920), MCI (277, HC (819) | Vitamin D binding protein (VDBP)is correlated with a score (inversely correlated with cognitive performance) | Targeted (Multiplex fluorescent immunoassay 177 utilizing coloured microspheres with protein-specific 178 antibodies) |
Bishnoi, 2015 [226] |
| AD (32), sMCI (13), other dementias (15) | Insulin-like growth factor-I (IGF-I) showed higher levels in AD and other dementias compared to HC and IGF-binding protein-3 (IGFBP-3) was increased in AD and sMCI compared to HC. In addition, IGF-I and IGFBP-3 correlated negatively with CSF β-amyloid. | Targeted (ELISA) | Johansson, 2013 [190] | ||
| MCI (3), AD (3), HC (3) | Proproteinconvertasesubtilisin/kexin type 9 (PCSK9), coagulation factor XIII, A1 polypeptide (F13A1), and dermcidin (DCD)are differentially expressed in MCI and AD. They could reflect PiB-PET imaging for MCI and AD | Targeted (NA) | Kang, 2016 [12] | ||
| AD (40), MCI (9), young controls (22), elderly controls (22) | Sirtuin1 (SIRT1) showed reduced levels with the age but this reduction is even more pronounced in MCI and AD. | Targeted (Surface Plasmon Resonance (SPR), Western-blot, ELISA) | Kumar, 2013 [167] | ||
| AD (156), HC (156) | 33 proteins: an eight-protein-based algorithm was the most robust with a sensitivity of 97.7%, specificity of 88.6%, and AUC of 99% | Targeted (Chemiluminescence) | Yu, 2018 [172] | ||
| AD (68), HC (52) | Peptides from Anthrax toxinreceptor 1, Nuclear protein 1, Glycogen phosphorylase, andOlfactory receptor 8J1 showed a statistically significant ability to discriminatebetween AD and HC | Untargeted (Biopanning and microarrays) | San Segundo-Acosta, 2019 [176] | ||
| AD (64), HC (45) | Increased concentrations of the presynaptic protein beta-synuclein in AD | Targeted (MS) | Oeckl, 2020 [177] | ||
| Plasma | Discovery cohort: 19 HC, 31 subjective memory concerns (SMC), 23 MCI, 6 AD. Replication cohort: 3 HC, 2 SMC, 25 AD, 49 FTD |
Proteomics: α2-Macroglobulin, fibrinogen γ-chain (FGG), and complement factor H-related protein 1 were associated with NAB. A model including FGG levels and age predicted NAB with a sensitivity of 59% and specificity of 78%. | Untargeted (LC-MS/MS) | Ashton, 2015 [191] | |
| AD (25), HC (25) | Proteomics: Several proteins showed differences between groups. Complement 4a plasma protein showed higher levels in AD. | Untargeted (LC-MS/MS, iTRAQ) | Bennett, 2012 [198] | ||
| MCI (10), AD (10), HC (10) | Redox proteomics: Haptoglobin was downregulated or increasingly oxidized in AD and MCI compared to HC. In addition, α2-macroglobulin, was selectively oxidized in AD compared with HC | Untargeted (Western-blot, MS) | Cocciolo, 2012 [192] | ||
| AD (207), HC (754) Validation: HC (58), AD (112) |
Proteomics: Panel of proteins differentially expressed between both groups. The validation with an external cohort showed an accuracy of 80%. | Untargeted (Plasma screening of 151 multiplexed analytes) | Doecke, 2012 [202] | ||
| AD (109), HC (58) | Proteomics: Set of 5 proteins differentiated between the AD and HC with a sensitivity of 89.36% and a specificity of 79.17%. | Untargeted (190-analyte multiplex immunoassay panel) |
Guo, 2013 [203] | ||
| AD (7), HC (7) | Proteomics: Twenty differentially expressed proteins between groups. Half of them are implied in amyloid/Aβ-peptide processing pathway | Untargeted (SDS-gel electrophoresis, ESI-MS) | Henkel, 2012 [156] | ||
| MCI-AD (163), HC (54) | Proteomics: Developed 11 signatures that discriminate between groups with sensitivity and specificity between 65-86%. | Untargeted (Fluorescent immunoassay) | Johnstone, 2012 [200] | ||
| Discovery: 195 subjects (93 twin pairs and 9 individuals). Replication: HC (91), MCI (81), AD (82). |
1129 proteins: Mitogen-activated protein kinase (MAPK) and MAPKAPK5 protein were associated with change in 10 years, and MAP2K4 were negatively correlated with volume of the left entorhinal cortex. These proteins could be potential biomarkers for AD conversion. | Untargeted (Slow Off-rate Modified Aptamer (SOMAmer)-based capture array called ‘SOMAscan’) | Kiddle, 2015 [159] | ||
| AD (9), HC (10) | Proteomics: Differential expression for proteins such as A-1, alpha-2-HS-glycoprotein, afamin, apolipoprotein A-4 and fibrinogen gamma chain between AD and HC. | Untargeted (2D-DIGE MALDI-TOF/TOF/MS) |
Kitamura, 2017 [28] | ||
| MCI (50), HC (50) | Proteomics: Keratin type-2 was up regulated, and albumin was down regulated in MCI | Untargeted (2D-PAGE MALDI-TOF/MS-MS) |
Kumar, 2018 [157] | ||
| Disease | Sample | Participants (n) | Biomarker and Results | Analytical Method | Refs. |
| AD | Plasma | AD (109), MCI (360), HC (58) | 146 analytes: 4 signatures using 4-5 proteins. Apolipoprotein A-II, apolipoprotein E, serum glutamic oxaloacetic transaminase, α-1-microglobulin, and brain natriuretic peptide were present in the 4 signatures. They differentiate AD from HC with a specificity of 85% and a sensitivity of 74%. None of them predict AD progression with a great accuracy. | Untargeted (Fluorescent immunoassay) | Llano, 2013 [193] |
| Cohort 1: MCI (261), AD (24), HC (411). Cohort 2: MCI (180), HC (153) |
Proteomics: Complement regulators C1 inhibitor and factor H, fibronectin, ceruloplasmin, vitamin D-binding, apolipoproteins AIV, B-100 and H showed lower levels in MCI | Untargeted (iTRAQ 2D LC-MSMS) |
Muenchhoff, 2015 [133] | ||
| AD (85), MCI (300), HC (49) | Proteomics: 5 proteins associated to brain structural changes could discriminate between AD and HC with a specificity of 57% and a sensitivity of 89%. | Untargeted (190 analyte multiplex immunoassay panel) | Nazeri, 2014 [186] | ||
| AD (90), stable MCI (37), MCI-AD (39), HC (69). | Proteomics: DC-SIGNR, Aurora kinase A, MIP-1α, RGM-A, BMP-RII, CD39, Kallikrein 14, Ck-β-8-1, VEGF, EphA1 and HCC-1 proteins were differentially expressed among groups and could be useful as biomarkers for AD progression. | Untargeted (Slow Off-rate Modified Aptamer (SOMAmer)-based capture array called ‘SOMAscan’) | Sattlecker, 2016 [160] | ||
| AD (331), MCI (149), HC (211) | Proteomics: 13 protein predicted AD with an AUC of 0.70 | Untargeted (Slow Off-rate Modified Aptamer (SOMAmer)–based capture array called “SOMAscan”) |
Sattlecker, 2014 [201] | ||
| MCI (396), AD (112), HC (58) | Proteomics: Pancreatic polypeptide and N-terminal protein B-type brain natriuretic peptide showed higher levels in AD and MCI. ApoE ε3/ε4 or ε4/ε4 alleles showed distinct profiles | Untargeted (Multiplex Immunoassay Panel) | Soares, 2012 [196] | ||
| aMCI (147), nMCI (114), AD (19), HC (411) | Proteomics: 30 proteins were differentially expressed between (AD or MCI) and HC. These proteins include inflammatory response, cholesterol transport and blood coagulation pathways | Untargeted (iTRAQ Two-dimensional liquid chromatography and MS/MS) |
Song, 2014 [197] | ||
| AD (79), MCI (88), HC (95) | Proteomics: Complement components C3 and C3a, complement factor-I, γ-fibrinogen and alpha-1-microglobulin with age and sex explain 35% of variance in whole brain volume in AD patients | Untargeted (2DGE and LC/MS/MS) | Thambisetty, 2011 [194] | ||
| Baltimore Longitudinal Study of Aging (57) | Proteomics: 18 proteins differentiate between individuals with high and low brain Aβ. ApoE protein was related to brain changes in AD. | Untargeted (2DGE and (LC/MS/MS)) | Thambisetty, 2010 [195] | ||
| non-demented older individuals (157) | Proteomics: A2M, Apo-A1, and multiple complement proteins could be potential pre-clinical biomarkers for AD. | Untargeted (2DGE and LC-MS/MS) | Westwood, 2016 [130] | ||
| MCI (119) | Proteomics: 60 discriminant proteins between groups predicted progressive MCI with an accuracy of 79%. | Untargeted (LC-MS/MS) | Yang, 2014 [135] | ||
| Cohort 1: AD (77), HC (50) Validation: AD (10), MCI (30), HC (10) |
1129 proteins: A diagnose model with 5 proteins was developed. It diagnoses AD with sensitivity of 100.0%, specificity of 80.0% and accuracy of 90.0%. MCI and pre-dementia were diagnosed with sensitivity of 96.7%, specificity of 80.0% and accuracy of 92.5% | Untargeted (The SOMAscan assay is based on protein capture slow off-rate modified aptamers) | Zhao, 2014 [131] | ||
| MCI (161), HC (378) | Higher levels of Tau in MCI than in HC, and it was also related to memory and cortical thickness | Targeted (ELISA) | Dage, 2016 [209] | ||
| MCI (29), mild AD (21), HC (23) | Phosphorylated tau protein (threonine 181), denoted p-tau181level is correlated more to AD severity than T-tau |
Targeted (Immunoassay) | Yang, 2018 [165] | ||
| AD (80), HC (37), behavioural variant frontotemporal dementia (bvFTD) (14) | Soluble amyloid precursor protein (sAPP)α and β. sAPPβ showed lower levels in AD compared to HC and bvFTD. | Targeted (ELISA) | Perneczky, 2013 [189] | ||
| MCI-AD (21), Dementia-AD (44), HC (27) | Further evidence for the potential of sAPPβ in plasma as an AD biomarker candidate | Targeted (ELISA) | Alexopoulos, 2018 [204] | ||
| Dementia due to AD (23), Dementia due to other reasons (17) | Aβ38, Aβ40 and Aβ42. the Aβ42/Aβ40 ratio in blood plasma as a promising AD biomarker candidate which correlates significantly with the validated core biomarkers of AD | Targeted (Chemiluminescenceimmunomultiplex assay) | Shahpasand-Kroner, 2018 [173] | ||
| AD (58), HC (61) | Aβ levels, and platelet count. Correlation indicates that platelets may be involved in the pathogenesis of AD and become a potential peripheral biomarker for AD | Targeted (ELISA) | Sun 2018 [205] | ||
| Disease | Sample | Participants (n) | Biomarker and Results | Analytical Method | Refs. |
| AD | Plasma | AD (24), HC (37) | Aβ oligomers. Higher levels in patients with AD than in HC, and they correlated well with conventional AD biomarkers | Targeted (ELISA) | Wang, 2017 [206] |
| AD (70), MCI (50), non-demented subjects with white matter hyperintensity (nd-WMH) (68), HC (33) | Protein-conjugated acrolein (PC-Acro) and amyloid-β40/42ratio detected MCI, AD and nd-WMH | Targeted (ELISA) | Waragai, 2012 [207] | ||
| Mild to moderate AD (10), MCI (20), patients who transitioned within 36 months from MCI to AD (20), HC (10) | P-tau, Aβ1-42, neurogranin (NRGN), and repressor element 1-silencing transcription factor (REST). Neuronally derived blood exosome proteins P-tau, Aβ1-42, NRGN, and REST could predict MCI to AD progression. | Targeted (ELISA) | Winston, 2016 [208] | ||
| AD (25), HC (20) | Neurogranin (Ng). There were identified 16 endogenous Ng peptides, but their levels were similar between both groups. | Targeted (nanoflow liquid chromatography- MS/MS) | Kvartsberg, 2015 [211] | ||
| MCI (13), AD (24), VaD (10), Mixed (8), other (5), HC (20) | Brain-derived neurotrophic factor (BDNF), Heart-type fatty acid-binding protein (FABP), Glial fibrillary acidic protein (GFAP), Interleukin-6 (IL6), Neuron-specific enolase (NSE), Neutrophil gelatinase-associated lipocalin (NGAL), Soluble tumor necrosis factor receptor I (TNFRI), D-dimer (DDMER), Thrombomodulin (TM), C-reactive protein (CRP). Some metabolites showed differences between groups. | Targeted (Arrays) | Rosén, 2011 [188] | ||
| AD (203), MCI (58), HC (117) | Lower levels of CRP in AD compared to HC and MCI | Targeted (ELISA) | Yarchoan, 2013 [210] | ||
| Dementia (80), aMCI (89), HC (133) | SUMO1 protein could be associated with AD as it showed increased levels in dementia patients and its levels correlate with MMSE | Targeted (ELISA) | Cho, 2015 [212] | ||
| MCI (49), AD (61), HC (35) | Higher levels of Chitinase 3-like 1 (CHI3L1) were found in AD compared to MCI and HC, while not differences were found between HC and MCI. | Targeted (ELISA) | Choi, 2011 [134] | ||
| AD (63), MCI (59), HC (63) | Cystatin C (CysC)levels were different among groups at baseline. | Targeted (ELISA) | Ghidoni, 2010 [214] | ||
| AD (126), vascular dementia (VaD)(96), non-AD neurodegenerative dementias (NND) (30), HC (98) | Soluble low-density lipoprotein receptor-related protein-1 (sLRP) showed lower levels in AD than the other groups, its sensitivity was 77.8% and its specificity was 93.3% for NND, 85.7% for HC and 58.3% for those with VaD. The soluble form of the receptor for advanced glycation end products (sRAGE)showed lower levels in AD compared with VaD or HC. AUC 0.88 with both protein levels. |
Targeted (ELISA) | Liang, 2013 [187] | ||
| AD (84) | Plasma prion protein (PrP)is not useful for AD progression monitorization | Targeted (EIA) | Schmidt, 2014 [129] | ||
| AD (40), non-demented (ND) (80) | Apolipoproteins. ApoA-I showed lower levels in AD and discriminated AD from ND with an AUC of 0.93. | Targeted (ELISA) | Shih, 2014 [213] | ||
| AD (257), HC (137) | Angiotensin-converting enzyme (ACE)levels were different between genotypes | Targeted (ELISA) | Yang, 2011 [163] | ||
| HC (92), MCI (527), AD (202) | A panel of proteins (n = 44), age and apolipoprotein E (APOE) ε4, predicted AD with good accuracy | Untargeted (SOMAscan assay) | Shi, 2020 [181] | ||
| AD (52), amnestic mild cognitive impairment (98), HC (114) | Level of sAPPβ was significantly increased in AD patients than in HC | Targeted (ELISA) | Yun, 2020 [182] | ||
| HC (408),MCI (400), AD (192) | A 7-protein panel could significantly discriminate between individuals with high and low amyloid pathology | Targeted (Luminex, ELISA, meso-scale discovery (MSD) assays) | Westwood, 2020 [183] | ||
| Early AD (33), Late AD (30), HC (36) | Elevation in markers GFAP and NfLin early AD | Targeted (SIMOA immunoassay) | Elahi, 2020 [220] | ||
| HC (186), MCI (50), AD (42)) | Proinflammatory endophenotypeidentify a specific subsetof adults with Down Syndromeand high risk of AD | Targeted (Meso-scale discovery assay) | Petersen, 2020 [199] | ||
| AD (186), HC (485), Validation cohort: AD (242), HC (199) |
CDH6 and HAGH may be new biomarkers in pre-symptomatic AD | Untargeted (affinity-based assay) | Ahmad, 2020 [178] | ||
| Blood | AD (106), HC (51) | 6-biomarker panel (A1Micro, A2Macro, AAT, ApoE, complement C3 and PPP) that discriminate between AD patients and HC with a sensitivity of 85.4% and specificity of 78.6%. | Untargeted (immunoassay platform and reference LC/MSMS(ADNI1)) | Jammeh, 2016 [228] | |
| Disease | Sample | Participants (n) | Biomarker and Results | Analytical Method | Refs. |
| AD | Blood | mild to moderate AD (72), MCI (33), HC (113). | Alpha-defensins 1 and 2levels were increased in AD | Untargeted (SELDI-TOF MS) | Watt, 2015 [155] |
| probable AD (7), HC (7). | Proteomics: Secretory (alpha) granule proteins showed lower levels in AD. Pathways as glycoprotein synthesis, lipid homeostasis, amyloidogenic proteins, and regulators of protease activity were altered in AD platelets. | Untargeted (SDS-PAGE, LC-MS/MS) | Donovan, 2013 [154] | ||
| MCI (5), AD (5), HC (5) | Proteomics: Thioredoxin-dependent peroxide reductase, myosin light polypeptide 6, and ATP synthase subunit β showed differential levels among groups | Untargeted (2D–PAGE, ESI-MS) | Sultana, 2013 [227] | ||
| MCI (34), AD (45), HC (28) | APP, β-APP cleaving enzyme 1 (BACE1), presenilin 1 (PS1) and a disintegrin and metalloproteinase-10 (ADAM-10). APP and ADAM-10 showed reduced levels in MCI and AD compared with HC. The ratio ADAM-10/BACE1 was higher for the MCI compared to AD |
Targeted (Western blot) | Bermejo-Bescós, 2013 [229] | ||
| MCI-AD (30), HC (23) | Amyloid-β protein precursor (AβPP) isoform (115 kDa) was increased in AD/MCI group compared to HC. | Targeted (Western-blot) | Jelic, 2013 [168] | ||
| AD (68), MCI (19), Old control (33), young control (11) | sAPP-α and sAPP-b. sAPP-β showed higher levels in MCI and AD compared to HC. |
Targeted (ELISA) | Marksteiner, 2013 [164] | ||
| AD (25), HC (26) | Amyloid protein precursor (APP), tau protein, clusterin, α-synuclein and immunoglobulin (Ig). Slightly elevated Ig levels in AD subjects (not significative) and APP-N measures were negatively correlated with cognitive scores. |
Targeted (ELISA) | Mukaetova-Ladinska, 2012 [232] | ||
| AD (65), HC (809) | Changes in amyloid structure biomarker indicates prodromal AD and correlates with CSF AD biomarkers and amyloid PET imaging | Targeted (ATR-FTIR analyses (attenuated total reflection Fourier transform infrared)) | Nabers, 2018 [233] | ||
| MCI (34), AD (21) | APP ratio (percentage of 120-130 kDa to 110 kDa isoforms of the amyloid precursor protein). MCI who converted to dementia showed lower levels for the ratio. The accuracy was 0.74 and sensitivity and specificity were 75% | Targeted (Western blot) | Zainaghi, 2012 [231] | ||
| MCI (398) | ApoE, BDNF, clusterin, IL-6R, IL-13, and TNF-α. Age, sex, education, hippocampal volume, APOE genotype, and plasma identify patients with brain amyloidosis with a sensitivity of 68% and a specificity 78%. |
Targeted (immunoassay platform and reference LC/MSMS(ADNI1)) | Apostolova, 2015 [234] | ||
| AD (38), HC (34) | Ischemia-modified albumin (IMA), advanced oxidation protein products (AOPP), ferric reducing antioxidant power (FRAP) and the prooxidant-antioxidant balance (PAB). AOPP, IMA and PAB showed elevated levels in AD group while FRAP showed lower levels. |
Targeted (Colorimetric assays) | Altunoglu, 2015 [235] | ||
| AD (30), MCI (30), HC (60) | Platelet monoamine oxidase-B, frequently described to be increased in platelets and brains of AD patients, shows a gender-independent but stage-related increase since it is unaltered in MCI subjects | Targeted (SDS-PAGE and western-blot) | Reumiller, 2018 [236] | ||
| AD (13), HC (27) | Platelet amyloid precursor protein (APP) ratio (120-kD and 130-kD isoforms compared to that of the 110-kD isoform) was lower in AD than HC. | Targeted (electrophoresis and immunoblot, densitometry) |
Srisawat, 2013 [230] | ||
| Late AD (27), late control (26), early AD (13), early control (17) | GLUT1 transporter and the insulin receptor (INSR). INSR from red blood cells (RBC) membrane are increased in AD compared to HC | Targeted (Flow citometry) | Várady, 2015 [175] | ||
| 303 participants and replicated in ADNI cohort (566 participants) | Alpha-2 macroglobulin is correlated with tau and p-tau and higher levels of this protein are related to AD progression. | Targeted (NA) | Varma, 2017 [132] | ||
| Platelets and leukocytes | AD (20), HC (20) | Combining the protein level of ADAM10, BACE1, and PSEN1 in platelets, yielded a good accuracy to discriminate AD from controls | Targeted (Western blot) | Bram, 2019 [169] | |
| aMCI (53), HC (45) | In aMCI the AβPP ratio level was significantly lower and levels of P-tau231 and Ser396/404 phosphorylated tau were significantly higher | Targeted (Western blot) | Shi, 2020 [166] | ||
| Tears | AD (14), HC (9) | Proteomics. Levels of lipocalin-1, dermcidin, lysozyme-C and lacritin could constitute a diagnosis tool with a sensitivity of 81% and a specificity of 77%. | Untargeted (SDS-PAGE, LC-MS/MS) | Kalló, 2016 [271] | |
| Disease | Sample | Participants (n) | Biomarker and Results | Analytical Method | Refs. |
| AD | AD (9), MCI (8), HC (15) | Elongation initiation factor 4E (eIF4E) as a unique protein present in AD | Untargeted (RP-LC-MS/MS) | Kenny 2019 [83] | |
| Saliva | AD (7), HC (27) | Amyloid-β Protein 42 salivary levels were elevated in AD compared to HC. This biomarker could be useful as AD diagnosis. | Targeted (ELISA) | Lee, 2017 [145] | |
| AD (15), HC (7). | Salivary beta amyloid 42 (Aβ42) levels were significantly higher in AD patients than in HC | Targeted (ELISA) | Sabbagh, 2018 [146] | ||
| Urine | AD (45), MCI (60), HC (65) | Alzheimer-associated neuronal thread protein (AD7c-NTP) were higher in AD and MCI compared to HC. | Targeted (ELISA) | Ma, 2015 [149] | |
| aMCI(23), naMCI group (23). | aMCI has higher levels of urinary AD7c-NTP | Targeted (ELISA) | Ku, 2019 [150] | ||
| AD (97), aMCI (50), HC (84) | MCP-1 levels weresignificantly higher in patients with AD and aMCI than in CN controls | Targeted (ELISA) | Xu, 2020[151] | ||
| PD | Serum | PD (81), other neurodegenerative diseases (39), HC (40) | Proteomics: 17 variables showed differences between groups. A model based on 5 biomarkers differentiate between PD and HC. | Untargeted (Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDITOF-MS)) | Li, 2011 [141] |
| Slight PD (8), middle to serious PD (8), HC (6) | Proteomics: 26 proteins were differentially expressed among groups | Untargeted (iTRAQ labelling, 2D-LC-MS/MS) | Zhang, 2012 [142] | ||
| PD (18), HC (7) | Proteomics: 15 differentially expressed proteins were found. Some of them are implied in antioxidation, lipid metabolism, intracellular transport, cell proliferation and immunoregulation pathways. | Untargeted (2-DE, ESI-Q-TOF-MS/MS) | Zhao, 2010 [239] | ||
| PD (51), HC (50) | High-sensitivity C-reactive protein (hs-CRP) and carcinoembryonic antigen (CEA) showed higher levels in PD compared to HC. | Targeted (hs-CRP nephelometric assay CEA: chemiluminescence immunoassay method) | Akıl, 2015 [174] | ||
| Early PD (63), HC (117) | High-sensitivity C-reactive protein (hs-CRP) showed higher levels in early PD. | Targeted (NA) | Song, 2011 [246] | ||
| Early PD (58), HC (20). | Interleukin (IL)-1β, IL-2, IL-6, IL-10, tumor necrosis factor-α, and high-sensitivity C-reactive protein. There is an increased peripheral inflammation in the early stage of PD, but the role of inflammation in motor and non-motor symptoms is unclear. | Targeted (ELISA) | Kim, 2018 [245] | ||
| PD (60), HC (45) | Higher levels of advanced oxidized protein products were observed in PD compared to HC | Targeted (LC/MS/MS) | García-Moreno, 2013 [140] | ||
| PD (18), HC (7) | DJ-1 protein may not be a biomarker of PD. In addition, there may be differences in the serum DJ-1 protein levels between Chinese and Japanese patients | Targeted (ELISA) | An, 2018 [237] | ||
| Sporadic idiopathic PD (213), progressive supranuclear palsy (PSP) (46), multiple system atrophy (MSA) (80), HC (177) | Expression of Rab35 was increased in PD compared to HC and other parkinsonian disorders, and it is also related to age at onset of PD. | Targeted (ELISA) | Chiu, 2016 [251] | ||
| PD (108), HC (31) | Caffeine, Theophylline, Theobromine, Paraxanthine, 1,7-Dimethyluric acid, 1,3,7-Trimethyluric acid, 1-Methylxanthine, 3-Methylxanthine, 1-Methyluric acid, 7-Methylxanthine, 5-acethylamino-6-formylamino-3-methyluracil, 5-acethylamino-6-amino-3-methyluracil. Lower levels of caffeine and caffeine metabolite profiles are promising diagnostic biomarkers for early PD. This is consistent with the neuroprotective effect of caffeine. | Targeted (LC-MS) | Fujimaki, 2018 [252] | ||
| PD (23), schizophrenia (17), HC (12) | Apolipoprotein E levels are higher in PD patients as compared with schizophrenic patients | Targeted (ELISA) | Gupta, 2018 [249] | ||
| PD (43), HC (40) | Serum levels of Tumor necrosis factor-α-induced protein-8 like-2(TIPE2) and its gene expression might be important prognostic biomarkers of PD. | Targeted (ELISA) | Kouchaki, 2018 [238] | ||
| PD (23), acute cerebral infarction (ACI, 30), HC (29) | Glial fibrillary acidic protein (GFAP) and neurofilament proteins (NFs) showed higher levels in PD and ACI than HC. Not differences were observed between AD and ACI. | Targeted (ELISA) | Su, 2012 [248] | ||
| Disease | Sample | Participants (n) | Biomarker and Results | Analytical Method | Refs. |
| PD | Early PD (106), HC (146) | CystatinClevels may predict the severities of sleep-disordered breathing problems in early PD patients | Targeted (Immunoturbidimetry assay) | Xiong, 2018 [171] | |
| PD (20), HC (10) | The expression levels of some proteins (complement C1q, protein Immunoglobulin Lambda Variable 1-33 (IGLV1-33)Cluster -33) were decreased in PD | Untargeted (MS) | Jiang, 2019 [242] | ||
| Plasma | PD (36), HC (16) | Proteomics: IgGκL and human serum amyloid P component (SAP) were found differentially expressed between groups. | Untargeted (2-DE analysis, LC/MS/MS) | Chen, 2011 [253] | |
| PD (58), HC (38) | Alpha-synuclein level is not valuable marker for AD | Targeted (ELISA) | Malec-Litwinowicz, 2018 [254] | ||
| PD (313) | CRP levels correlate with death risk in PD patients and it could serve as prognosis biomarker. | Targeted (NA) | Sawada, 2015 [136] | ||
| PD (375) | CRP levels could serve as prognosis biomarker for motor deterioration in PD. | Targeted (NA) | Umemura, 2015 [137] | ||
| tremor-dominant PD (TD-PD) (33), non-tremor dominant PD (NT-PD) (43) | The elevated plasma transferrin level, combining with decreased plasma iron level might be given considerable weight in the recognition of parkinsonian tremor. | Targeted (Scatter turbidimetry) | Si, 2018 [255] | ||
| PD (145), HC (45) | N8-acetylspermidine and N-acetylputrescine levels were significantly and mildly elevated in PD, respectively | Untargeted (Capillary Electrophoresis Time-of-Flight MS) | Saiki, 2019 [241] | ||
| PD (12), HC (12) | Proteins CCDC154, TRIM3, DHH, NRP2 and CLIC1 were detected with high specificity and sensitivity | Untargeted (liquid chromatography-mass spectrometry (LC-MS)) | Dong 2019 [250] | ||
| PD (96), HC (45) | Proteins (BSP, OMD, ACY1, GHR) robustly associated with PD | Untargeted (SOMAscanassay) | Posavi, 2019 [243] | ||
| PD (64), HC (30) | Aβ42 and tau protein inPD may be useful marker for cognitive impairments | - | Chojdak-Łukasiewicz, 2020 [244] | ||
| Blood | PD (9), HC (9) | Proteomics. Diagnosis model-based peptides from a protein signature achieved an AUC of 0.877. | Untargeted (LC-MS/MS) | Alberio, 2014 [256] | |
| PD (43), progressive supranuclear palsy (PSP, 13), MSA (8), HC (16) | Oxidized DJ-1 protein levels in erythrocytes can be used as a marker for the differential diagnosis of PD | Targeted (ELISA) | Yamagishi, 2018 [258] | ||
| PD (16), HC (8) | Clusterin, complement C1r subcomponent, and apolipoprotein A1. The expression levels of apolipoprotein A1 in exosomes may be useful for tracking the progression of PD. | Targeted (2D-DIGE analysis, MALDI-TOF/TOF/MS) | Kitamura, 2018 [257] | ||
| PD (53), HC (53) | heat shock cognate (hsc) 70 protein and lysosomal-associated membrane protein (lamp) 2A. Hsc70 levels were reduced in PD patients. | Targeted (Western blot) | Sala, 2014 [143] | ||
| Early PD (103), HC (156) | Mitochondrial ribosomerecycling factor (MRRF) and ribosomal protein S18 (RPS18), distinguished betweenPD and HC | Untargeted (Microarray) | Wu, 2020 [247] | ||
| Blood derived extracellular vesicles | PD (60), HC (37) | Proteomics: Proteomic analysis further revealed that there is a specific signature of proteins that could reliably differentiate HC from mild and moderate PD patients | Untargeted (nanoLCMS/MS) | Lamontagne-Proulx, 2019 [144] | |
| Tears | PD (36), HC (18) | Proteins from S100 superfamily (i.e. [S100A7], [S100A8] and [S100A11]), Peroxiredoxin-6 [PRDX6], Annexin-A5 [ANXA5] and Glutathione S-transferase-A1 [GSTA1] were upregulated in PD | Untargeted (Bottom-up liquid chromatography electrospray ionization tandem mass spectrometry (BULCMS)) | Boerger, 2019 [153] | |
| Saliva | PD (20), HC (20) | α-synuclein could serve as PD diagnosis biomarker showing lower levels in PD compared to HC. | Targeted (ELISA) | Al-Nimer, 2014 [147] | |
| PD (16), HC (22) | DJ-1and total proteins showed elevated levels in PD patients. Saliva could be useful for protein biomarker research. | Targeted (Western blot) | Masters, 2015 [148] | ||
| Urine | PD (28), HC (22) | SNAP23 and calbindin were the most elevated in PD | Untargeted (Mass spectrometry) |
Wang, 2019 [240] |