Table I.

Possible blood-derived markers for identifying the risk of MCI and AD.

Study	Methods	Identified biomarkers	AD (n)	MCI (n)	Control (n)	Refs. (n)
Borroni et al, 2003	Western blot analysis	Decreased baseline platelet APP predicted progression from MCI to AD	–	30	–	13
Zetterberg et al, 2013	Tau5, HT7 and BT2 monoclonal antibodies	Higher tau levels in AD	54	75	25	20
Zhang et al, 2014	Post-mortem autopsy	Deletion of the AEP gene substantially reduced tau hyperphosphorylation	8	–	8	21
Mapstone et al, 2014	LASSO analysis	ApoE ε4 was similar in MCI and AD	18	35	53	22
Whiley et al, 2014	LC-MS and MLV	Three PCs were significantly lower in AD	75	82	84	23
Marksteiner et al, 2014	Multiplex array or ELISA	27 vascular-related proteins; NT-proBNP was significantly increased in AD and MCI	43	27	40	25
Hye et al, 2014	Multiplex (xMAP) assays	10 plasma proteins (ApoC3, TTR, A1AT, PEDF, CC4, ICAM 1, RANTES, A1AcidG, cystatin C, clusterin) were associated with disease severity and progression	476	220	452	26
Lane et al, 2008	ELISA, MRI	MCI with ApoE ε4 and BCHE-K progressed to AD	–	464	–	27
Soares et al, 2012	Multiplex immunoassay panel	Increases in eotaxin 3, pancreatic polypeptide, NT-proBNP and TN-C; decreases in IgM and ApoE levels in patients with AD and MCI; Apo ε3/ε4 or ε4/ε4 carriers had low C-reactive protein and ApoE levels, and high cortisol, interleukin-13, apolipoprotein B and gamma interferon levels	97	345	54	28
Sattlecker et al, 2014	SOMAscan	PSA-ACT, pancreatic prohormone, clusterin and fetuin B were related to AD	331	149	211	29
Craig-Schapiro et al, 2010	2-D DIGE LC-MS/MS and ELISA	YKL-40, a putative indicator of neuroinflammation, is elevated in AD, and together with Aβ42, has potential prognostic use as a biomarker for preclinical AD	48 (with FTD and other dementia)	–	–	31
Mangialasche et al, 2013	HPLC	Vitamin E measures enchanced the accuracy of sMRI differentiating patients with AD and MCI from cognitively healthy subjects	81	86	86	33
Squitti et al, 2009	Spectrophotometry and immunoturbidimetry assay	Higher baseline levels of free copper were correlated with severe cognitive decline in AD and more obvious disabilities at 1 year	81	–	–	36
Pavlopoulos et al, 2013	Post-mortem human autopsy and mouse study	RbAp48 decline is responsible for age-related memory loss	8	–	–	37
Nettiksimmons et al, 2015	ELISA and INNO BIA assays	Higher risk index of blood markers (telomere length, cystatin, serum glucose, C-reactive protein, albumin, IL-6, ApoE ε4 and Aβ42/40) exhibited severe cognitive decline	–	–	739	39
Apostolova et al, 2015	Luminex, quantitative polymerase chain reaction	ApoE genotype, plasma levels of IL-6R and clusterin were useful for predicting brain amyloidosis; ApoE genotype and plasma IL-6R were useful for predicting the conversion of MCI to AD	–	211	–	40

MCI, mild cognitive impairment; AD, Alzheimer's disease; APP, amyloid precursor proteins; ELISA, enzyme-linked immunosorbent assay; MRI, magnetic resonance imaging; ApoE, apolipoprotein E; BCHE-K, butyrylcholinesterase K-variant; 2-D DIGE, 2-D Fluorescence Difference Gel Electrophoresis; LC-MS, liquid chromatography-mass spectrometry; YKL-40, chitinase-3-like-1; Aβ, amyloid-β; FTD, frontotemporal dementia; NT-proBNP, N-terminal pro-brain natriuretic peptide; TNC, tenascin C; IgM, immunoglobulin M; IL-6, interleukin 6; IL-6R, interleukin 6 receptor; HPLC, reverse-phase high-performance liquid chromatography; HT7 and BT2, anti-tau monoclonal antibody; LASSO, ligand activity by surface similarity order; MLV, multiplatform lipidomic validation; PC, phosphatidylcholine; TTR, transthyretin; A1AT, alpha-1 antitrypsin; PEDF, pigment epithelium-derived factor; CC4: complement C4; ICAM-1, intercellular adhesion molecule 1, RANTES, regulated on activation normal T cell expressed and secreted; A1AcidG, alpha-1-acid glycoprotein; PSA-ACT, prostate-specific antigen complexed to α1-antichymotrypsin; AEP, asparagine endopeptodase.