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

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