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Table 1 Proteomic approaches, sample size and neuropsychological criteria for the groups used in the studies included

From: A comprehensive systematic review of CSF proteins and peptides that define Alzheimer’s disease

No Author and year Proteomic approach Controls samples AD samples Mean age (controls) Mean age (AD) Neuropsychological criteria CSF biomarkers (control) CSF biomarkers (AD)
1 Whelan CD et al. (2019) [86] Olink™ ProSeek immunoassay 565 176 72 74.6 NINCDS-ADRDA criteria, MMSE score and CSF biomarkers Mean Aβ42 [pg/ml(SD)]: 752(253)
Mean Aβ40 [pg/ml(SD)]: 5847(2042)
Aβ42/40 ratio - log2 transformed (SD): 2.05(0.17)
Mean total tau [pg/ml(SD)]: 292(89)
Mean phospho-tau [pg/ml(SD)]: 37(13)
Mean Aβ42 [pg/ml(SD)]: 305(132)
Mean Aβ40 [pg/ml(SD)]: 5470(2179)
Aβ42/40 ratio - log2 transformed (SD): 2.9(0.29)
Mean total tau [pg/ml(SD)]: 649(221)
Mean phospho-tau [pg/ml(SD)]: 123(47)
2 Khoonsari et al. (2019) [87] Nano LC-MS/MS (7 T hybrid LTQ FT MS) 45 76 88 72 NINCDS-ADRDA criteria, DSM-IV criteria, MMSE and CSF biomarkers Aβ42 ng/l (Median[range]): 676(337–1343)
p-tau ng/l (Median[range]) 414 (202–1121)
t-tau ng/l (Median[range]): 63 (29-122)
Aβ42 ng/l (Median[range]): 405(160–1160)
p-tau ng/l (Median[range]) 82 (28–220)
t-tau ng/l (Median[range]): 617 (160–1720)
3 Sathe et al. [88] High-Resolution MS, TMT multiplexing technology and targeted PRM analysis 5 5 71 71.6 CDR, MOCA, CSF biomarkers and NIA-AA criteria Mean Aβ42 [pg/ml(SD)]: 1185.86(389.29) Mean Aβ42 [pg/ml(SD)]: 402.11(189.62)
4 Duits et al. (2018) [89] PRM 40 40 64.5 64.6 MMSE, clinical evaluation, and CSF biomarkers Mean Aβ42 [pg/ml(SD)]: 1086(161)
Mean total tau [pg/ml(SD)]: 228(64)
Mean phospho-tau [pg/ml(SD)]: 40(9)
Mean Aβ42 [pg/ml(SD)]: 640(91)
Mean total tau [pg/ml(SD)]: 740(433)
Mean phospho-tau [pg/ml(SD)]: 94(47)
5 Dayon et al. (2018) [90] RP LC-MS/MS 48 72 66 73.7 CDR, APOEa genotype and CSF biomarkers Mean Aβ42 [pg/ml(SD)]: 957.4(194)
Mean total tau [pg/ml(SD)]: 221.5(82.9)
Mean phospho-tau [pg/ml(SD)]: 45.9(13.3)
Mean phospho-tau (SD)/Aβ42: 0.049(0.015)
Mean Aβ42 [pg/ml(SD)]: 774(281.5)
Mean total tau [pg/ml(SD)]: 471.1(316.6)
Mean phospho-tau [pg/ml(SD)]: 72.7(40.9)
Mean phospho-tau (SD)/Aβ42: 0.114(0.097)
6 Brinkmalm et al. (2018) [14] PRM-MS analysis and previously nanoflow LC-MS/MS 15 10 64.9 62.7 Clinical evaluation, computer tomography (CT) scan and CSF Aβ42 Mean Aβ42 [pg/ml(SD)]: 877.2(206.3) Aβ42 < 400 pg/ml;Mean Aβ42 [pg/ml(SD)]: 275.4(106.8)
7 Skillbäck et al. (2017) [45] Quantification-driven proteomic 40 40 64.5 64 NIA and IWG-2 criteria, CSF biomarkers and MMSE Information extracted from graphs:
Mean Aβ42 [pg/ml]: 950
Mean total tau [pg/ml]: 260
Mean phospho- tau [pg/ml]: 55
Information extracted from graphs:
Mean Aβ42 [pg/ml]: 450
Mean total tau [pg/ml]: 600
Mean phospho- tau [pg/ml]: 85
8 Wang et al. (2016) [46] LC-MS/MS and lectin-enrichment chromatography 4 4 74 75.7 Neuropsychological tests NI
9 Paterson et al. (2016) [91] Targeted proteomics: MRM-based triple quadrupole mass spectral assay 36 46 58.5 62.9 APOE# genotype and CSF biomarkers Mean Aβ42 [pg/ml(SD)]: 960(291)
Mean total tau (range): 234.5(174.5–315.5)
Mean phospho-tau [pg/ml(SD)]: 35.5(13.2)
Mean phospho-tau (range)/Aβ42: 0.25(0.19-0.33)
Mean Aβ42 [pg/ml(SD)]: 408(2168)
Mean total tau (range): 947(760–1196-315.5)
Mean phospho-tau [pg/ml(SD)]: 107.5(38.12)
Mean phospho-tau (range)/Aβ42: 2.5(1.8-4.1)
10 Remnestal et al. (2016) [92] Suspension bead array: HPA antibodies targeting the 280 proteins 38 72 58 77.4 NINCDS-ADRDA criteria and CSF biomarkers Mean Aβ42 [pg/ml(range)]: 706(559-1192)
Mean total tau (range): 308(171-399)
Mean phospho-tau (range): 47(29-60)
Group AD1: Mean Aβ42 [pg/ml(range)]: 350(160-950)
Mean total tau (range): 600(210–2430)
Mean phospho-tau (range): 78(34–282)Group AD2: Mean Aβ42 [pg/ml(range)]: 453(260–639)
Mean total tau (range): 834(190–3178)
Mean phospho-tau (range): 86(59–179)
11 Khoonsari et al. (2016) [16] RP nano LC- MS/MS andantibody suspension bead arrrays 10 10 88.2 79.4 Clinical evaluation, CSF biomarkers and MMSE NI Mean Aβ42 [ng/l]: 420.1
Mean total tau [ng/l]: 652.1
Mean phospho-tau [ng/l]: 132.2
12 Domenico et al. (2016) [93]** 2-DE - WB - MS (2-DE gel/carbonyl immunoblot) 6 6 NI NI NINCDS-ADRDA criteria, neuropsychological test and APOE# genotype NI
13 Heywood et al. (2015) [94] Label-free proteomic analyses (2-DE LC-MS) and Targeted proteomics: MRM-based triple quadrupole mass spectral assay 15 16 61 68.1 CSF biomarkers Mean Aβ42 [pg/ml(SD)]: 905.41(237)
Mean total tau [pg/ml(SD)]:136.58(162)
Mean phospho-tau [pg/ml(SD)]: 19.33(11.11)
Mean Aβ42 [pg/ml(SD)]: 503.68(165.8)
Mean total tau [pg/ml(SD)]:733.77(481.25)
Mean phospho-tau [pg/ml(SD)]: 93.38(31.55)
14 Hendrickson et al. (2015) [20] RP nano-HPLC coupled to an LTQ-FTMS hybrid mass spectrometer. SRM-MS 30 30 69 70 NINCDS-ADRDA criteria and APOE# genotype NI
15 Spellman et al. (2015) [95] LC/MRM-MS 85 66 75.6 75 APOE# genotype, CSF biomarkers and MMSE Mean Aβ42 [SD]: 207.8(56.26)
Mean phospho-tau (SD): 24.19(12.02)
Mean Aβ42 [SD]: 141.12(37.39)
Mean phospho-tau (SD): 41.95(20.6)
16 Hölttä et al. (2015) [15] TMT, LC−ESI MS, LC−MALDI MS 8 8 65 77 DSM-IIIRand NINCDS-ADRDA criteria Mean Aβ42 [pg/ml(range)]: 700(545–817)
Mean total tau (range): 405(330–523)
Mean Aβ42 [pg/ml(range)]: 235(210–298)
Mean total tau (range): 800(717–925)
17 Leung et al. (2015) [96] MAP-RBM platform (XMAP Luminex platform) /ELISA 325 344 71.7 74 MMSE, CDR, NINDS-ADRDA criteria and CSF biomarkers Aβ42 > 192 pg/ml Aβ42 < 192 pg/ml
18 Khan et al. (2015) [97]** XMAP Luminex platform 88 65 75.8 74.6 APOE# genotype, CSF biomarkers, and MMSE Mean Aβ42 [(SD)]: 205.7(57.2)
Mean total tau (SD):69.2(27.9)
Mean phospho-tau (SD): 24.9(13.2)
Mean Aβ42 [(SD)]: 140.4(35.3)
Mean total tau (SD):125.9(60.3)
Mean phospho-tau (SD): 42.2(20.7)
19 Oláh et al. (2015) [98] Master Antibody Microarray and WB 25 25 74.5 72 Clinial evaluation, NINCDS-ADRDA criteria, APOE# genotype and CSF biomarkers Mean Aβ42 [pg/ml(SD)]: 794(20)
Mean total tau [pg/ml(SD)]: 341(171)
Mean phospho-tau [pg/ml(SD)]: 23(2)
Aβ42 < 500 pg/ml total tau >600 pg/ml phospho-tau>60 pg/ml
20 Alzate et al. (2014) [99] MS and MS/MS and 2-DE multiplexed WB 7 11 AR: 62.8 to 81.5 AR: 62.8 to 81.5 APOE# genotype NI
21 Wildsmith et al. (2014)[100] LC-MS/MS, Targeted LC-MRM and ELISA 10 45 68.5 77.5 MMSE and CSF biomarkers Information extracted from graphs:
Mean Aβ42 [pg/ml]: 650
Mean total tau [pg/ml]: 60
Mean phospho- tau [pg/ml]: 25
Information extracted from graphs:
Mean Aβ42 [pg/ml]: 400
Mean total tau [pg/ml]: 150Mean phospho- tau [pg/ml]: 60
22 Chakrabarti et al. (2014) [101] 2-DE, MALDI MS Analysis and co-immunoprecipitation 11 11 67 71 NINCDS-ADRDA criteria, DSM-IV criteria, MMSE, CDR and other tests NI
23 Choi et al. (2013) [49]** Nano LC-MS/MS and nano LC-MRM/MS and ELISA 3 3 NI NI Confirmed by autopsy NI
24 Wijte et al. (2012) [102] MALDI TOF/TOF MS 20 20 77.7 75.95 Postmortem neuropathological evaluation NI
25 Ringman et al. (2012) [103] MS/MS, 2-DE LC/MS 5 4 37.6 34.2 CDR and FAD mutation carriers (MCs) and related noncarrieres (NCs)Π. APOE# genotype and CSF biomarkers Mean Aβ42 [pg/ml(SD)]: 618.4(100.1) Mean total tau [pg/ml(SD)]: 50.5(9.4)
Mean phospho-tau [pg/ml(SD)]: 24.6(9.2)
Mean Aβ42 [pg/ml(SD)]: 277.1(162.9) Mean total tau [pg/ml(SD)]: 140(59.9)
Mean phospho-tau [pg/ml(SD)]: 67(29)
26 Manral et al. (2012) [104] 2-DE and Nano LC-ESI-Q-TOF MS/MS system 8 8 60.7 62.6 NINCDS-ADRDA criteria, MMSE score and MRI NI
27 Vafadar-Isfahani et al. (2012) [105] nLC-MALDI-TOF MS/MS and MALDI TOF/TOF MS 23 33 NI NI NINCDS-ADRDA criteria, DSM-IV and MMSE and clinical evaluation Information extracted from graphs:
Mean Aβ42 [pg/ml]: 440
Mean Aβ40 [pg/ml]: 5000
Mean total tau [pg/ml]: 500
Information extracted from graphs:
Mean Aβ42 [pg/ml]: 190
Mean Aβ40 [pg/ml]: 3900
Mean total tau [pg/ml]: 2000
28 Jahn et al. (2011) [44] CE-MS and MS/MS 17 34 58.9 69 NINCDS-ADRDA criteria, CSF biomarkers and MMSE score NI Mean Aβ42 [pg/ml]: 300.91
Mean total tau [pg/ml]: 541.21
Mean phospho-tau [pg/ml]: 81.84
29 Craig-Schapiro et al. (2011) [106]** ELISA (targeted) 242 28+63 71.6 76.8 NINCDS-ADRDA criteria and CDR NI
30 Perrin et al. (2011) [50] 2-DE DIGE / nano- LC-MS/MS 198 29 71 76.5 CDR, MMSE score and CSF biomarkers Mean Aβ42 [pg/ml(SD)]: 605(240) Mean total tau [pg/ml(SD)]: 304(161)
Mean phospho-tau [pg/ml(SD)]: 55(25)
Mean Aβ42 [pg/ml(SD)]: 351(118)
Mean total tau [pg/ml(SD)]: 552(263)
Mean phospho-tau [pg/ml(SD)]: 77(38)
31 Hu et al. (2010) [107]** XMAP Luminex platform 33 66 NI NI MMSE, CSF biomarkers and confirmed by autopsy NI
32 Maarouf et al. (2009) [108] 2-DE DIGE and MS 43 47 84 79 APOE# genotype, CERAD and the NIA-Reagan Institute NI
33 Yin et al. (2009) [109] 1-DE and LC–MS/MS 6 5 55.3 71 NINCDS-ADRDA criteria NI
34 Zhang et al. (2008) [110] Immunobead-based multiplex assays 95 48 63 70 Clinical evaluation NI
35 Jung et al. (2008) [66] 2-DE, DE-MALDI-TOF MS 30 27 73.2 77.7 NINCDS-ADRDA criteria and CDR NI
36 Simonsen et al. (2007) [111] MS 32 85 68.3 69.15 NINCDS-ADRDA criteria, MMSE score and clinical evaluation NI
37 Hu et al. (2007) [112]** 2-DE DIGE, MS/MS and ELISA 55 19 NI NI CSF biomarkers, CDR and clinical evaluation Information extracted from graphs:
Mean Aβ42 (range): 1(0–2)
Mean total tau (range): 0.9(0–5)Mean phospho- tau (range): 0.8(0–5)
Information extracted from graphs:
Mean Aβ42 (range): 0.6(0–2)
Mean total tau (range): 1.9(0–5)Mean phospho- tau (range): 1.1(0–5)
38 Korolainen et al. (2007) [113] 2-DE and Nano LC-MS/MS 8 11 64.7 73.54 APOE# genotype, NINCDS-ADRDA criteria and MMSE score NI
39 Finehout et al. (2007) [114] 2-DE and TOF/TOF MS 12 44 NI NI Postmortem confirmation NI
40 Simonsen et al. (2008) [115] SELDI-TOF MS 72 95 73.1 72.5 NINCDS-ADRDA criteria, MMSE score and CSF biomarkers Group C1: Mean Aβ42 [pg/ml(SD)]: 876(209.2)
Mean total tau (SD): 295.8 (153.6)
Group C2: Mean Aβ42 [pg/ml(SD)]: 748.9(155.3)
Mean total tau (SD): 332.9 (158.7)
Group AD1: Mean Aβ42 [pg/ml(SD)]: 524.6(170.1)
Mean total tau (SD): 739.1 (300.9)
Group AD2: Mean Aβ42 [pg/ml(SD)]: 464(187.7)
Mean total tau (SD): 657.7 (339.4)
41 Castaño et al. (2006) [116] 2-DE and MALDI-TOF MS 43 43 81 81 Clinical diagnosis, Braak stages, and CERAD NI
42 Abdi et al. (2006) [52] iTRAQ labeling and 2-DE LC, MS/MS and WB 10 10 67 72 MMSE, CDR, NINDS-ADRDA criteria and other test NI
43 Selle et al. (2005) [117] MALDI-TOF-MS 102 140 62.5 71 ICD-10, NINCDS-ADRDA criteria, DSM-IV and MMSE NI
44 Zhang et al. (2005) [118]** LC-MS ICAT 20 32 70.5 71 MMSE and CDR NI
45 Puchades et al. (2003) [68] 2-DE and MALDI-TOF MS 7 7 66 80 NINCDS-ADRDA criteria and MMSE score NI
46 Carrette et al. (2003) [119] SELDI-TOF MS using SAX2 Protein-chip arrays 10 19 78 75 NINCDS-ADRDA criteria NI
47 Davidsson et al. (2002) [120] 2-DE, SYPRO Ruby staining and MS 12 15 67.3 77.2 NINCDS-ADRDA criteria and MMSE score NI
    Total samples (Control) Total samples (AD) Average age (Control) Average age (AD)    
    2562 2022 70 73    
  1. ESI electrospray ionization, MRM multiple reaction monitoring, PRM parallel reaction monitoring, MS mass spectrometry, TMT tandem mass tag, RP-LC MS/MS reversed-phase LC-MS/MS, SRM reaction monitoring, CE-MS capillary electrophoresis mass spectrometry, SELDI-TOF-MS surface enhanced laser desorption/ionization time-of-flight mass spectrometry, WB Western Blot, AR age range, NI not information, CDR Clinical dementia rating scale, MOCA Montreal cognitive assessment, NINCDS-ADRDA National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association, MMSE Mini-menta state exam, DSM Diagnostic and Statistical, FAD familial Alzheimer Disease, CERAD Consortium to Establish a Registry for Alzheimer’s Disease, ICD-10 10th revision of the International Statistical Classification of Diseases and Related Health Problems, IWG-2  International Working Group-2 criteria
  2. #Studies based on APOE genotype
  3. ΠStudy based on PSEN1 and APP mutations (this study was not considered to calculate the average age)
  4. ** Qualitative and not quantitative data