Table 1.

Blood biomarkers and VCID.

Author, Year [Reference]	Population	Biomakers	Outcome	Results
Murr J et al., 2014 [17]	670 cognitively normal subjects	Plasma oxidized low-density lipoprotein (OxLDL) levels	Risk Factor follow-up: 4.8 years (2.2–10.3)	No association between OxLDL and risk of all-cause dementia, AD, and vascular dementia or subtypes was found.
Dong H et al., 2015 [18]	127 AD patients, 30 MCI and 30 VaD patients.	Serum circulating miRNAs	Differential diagnosis	The panel of miR-31, miR-93 and miR-146a can be used to discriminate AD from VaD.
Duits FH et al., 2015 [19]	52 AD patients, 24 VaD patients, 26 cognitively normal subjects.	Plasma and CSF levels of MMP2, MMP9, MMP10, TIMP1 and TIMP2. CSF levels of amyloid-β(1–42) (Aβ42), tau, and tau phosphorylated at threonine-181 (p-tau).	Differential diagnosis	AD patients showed higher plasma MMP2 levels compared to VaD patients (p < 0.05).
Hatanaka H et al., 2015 [20]	72 AD, 27 VaD, 24 Mixed Dementia (MD) patients and 53 cognitively normal subjects.	Plasma levels of diacron reactive oxygen metabolite (dROM) and biological anti-oxidant potential (BAP).	Differential diagnosis	The dROM levels were significantly higher in the AD and MD groups than in the control group. The BAP levels were significantly lower in the MD group than in the control, AD and VaD groups.
Hilal S et al., 2015 [21]	41 cognitive impairment with no dementia (CIND) subjects and 46 demented subjects with burden of cerebrovascular diseases (CeVD); 37 CIND and 34 cases with dementia without CeVD; 35 cognitively normal subjects.	Plasma NTpro-BNP and high sensitivity cardiac troponin T (hs-cTnT) levels.	Differential diagnosis	Plasma concentrations of hs-cTnT were associated significantly with CeVD in both CIND and dementia. NTpro-BNP was associated with dementia with CeVD
Teunissen CE et al., 2015 [22]	295 subjects including healthy controls (n = 65), patients with subjective memory complaints (n = 99), patients with AD (n = 100), and patients with vascular dementia (n = 31).	Serum leptin levels	Differential diagnosis	Serum leptin levels are not altered in AD or vascular dementia patients compared to healthy controls and were not related to cognitive decline.
Wang C et al., 2015 [23]	10 cognitively healthy subjects and 10 age-matched VaD subjects.	Differentially expressed proteins (DEPs)	Differential diagnosis	High-degree proteins were detected in the protein-protein (PPI) interaction network, such as ATP5B (ATP synthase subunit β) in VaD.
Castellazzi M et al., 2016 [24]	232 MCI, 65 VaD, 175 AD, 88 MD, 104 Multiple Sclerosis (MS) patients, 165 cognitively healthy controls.	Serum High-density lipoprotein (HDL)-bound paraoxonase-1 (PON-1) levels	Differential diagnosis	Serum arylesterase, but not paraoxonase, levels were significantly lower in patients affected by MCI, VaD, AD, MD as well as those with MS as compared to healthy controls.
Chen Z et al., 2016 [25]	52 subcortical ischemic vascular disease patients with no dementia (SIVDND), 55 patients with mild cognitive impairment (SVMCI), 54 patients with vascular dementia (VaD), 54 cognitively healthy controls.	Serum thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), free triiodothyronine (FT3), total thyroxine (TT4) and free thyroxine (FT4), thyroglobulin antibody (TGA), and antithyroid peroxidase antibody (TPO-Abs).	Correlation with cognitive status	Serum TT3 and FT3 levels decreased, whereas serum TSH level increased, with the decline in cognitive functions in SIVD.
Dukic L et al., 2016 [26]	235 participants, divided in 4 groups: AD (N = 70), VaD (N = 67), MCI (N = 48) and Cognitively Healthy Participants (N = 50).	Serum kallikrein 6 (KLK6), clusterin (CLU), adiponectin (ADPN) and interleukin-6 (IL-6)	Differential diagnosis	Serum concentrations of KLK6, CLU and ADPN did not differ between AD, VaD, MCI and cognitively healthy control group of participants, whereas IL-6 was significantly higher in VaD patients than in AD, MCI and healthy individuals.
Horvath I et al., 2016 [27]	40 nondemented controls, 11 stable mild cognitive impairment (SMCI), 6 MCI due to AD (MCI-AD), 40 AD and 7 VaD.patients.	CSF concentration of Aβ1−42, S100A8, S100A9 and Tau.	Differential diagnosis	The S100A9 and Aβ1−42 levels correlated with each other: their CSF content decreased already at the SMCI stage and declined further under MCIAD, AD, and VaD conditions.
Kitagawa K et al., 2016 [28]	466 cognitively healthy subjects	serum high-molecular-weight (HMW) adiponectin level	Risk factor (median follow-up period: 6.9 years)	Risks of dementia in patients with high versus low HMW adiponectin levels were almost identical. No association was found between adiponectin levels and Alzheimer’s disease dementia or vascular dementia in the whole group or amongst men and women separately.
Levada OA et al., 2016 [29]	21 patients with AD; 22 patients with subcortical vascular dementia; 16 cognitively healthy subjects.	Plasma levels of brain-derived neurotrophic factor (BDNF)	Differential diagnosis	At baseline there was lower BDNF levels in both AD and VaD groups, which was significant only in subjects with AD.
Mirza SS et al., 2016 [30]	357 AD patients; 32 VaD patients.	Serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels	Risk factor	Higher NT-proBNP was associated with a higher risk of dementia, with a particularly strong association with vascular dementia.
Nilsson ED et al., 2016 [31]	374 incident dementia cases: 120 AD patients, 84 VaD and 102 MD patients.	Plasma level of copeptin	Risk factor (median follow-up period: 4.2 years)	Baseline level of copeptin predicted incident VaD.
Pan X et al., 2016 [32]	Exploration phase: 338 control subjects and 43 AD patients; Validation phase: 861 control subjects, 81 AD patients, 70 vascular dementia patients and 13 frontotemporal dementia patients.	Blood Thiamine diphosphate (TDP), thiamine monophosphate, and thiamine levels	Differential diagnosis	TDP exhibited significant and consistent values for AD diagnosis in both exploration and validation phases. TDP can effectively distinguish AD from vascular dementia.
Bednarska-Makaruk M et al., 2017 [33]	205 patients with dementia (89 with AD, 47 with VaD, 69 with mixed dementia (MD)), 113 persons with MCI and 107 controls.	Serum adiponectin, leptin and resistin levels, IL-6, CRP, chitotriosidase, 25-OH vitamin D, HDL-cholesterol and paraoxonase 1, glucose, insulin and HOMA-IR.	Differential diagnosis	Vascular and mixed dementia are characterized by an increase of resistin. Positive correlation of resistin with inflammation indicators may suggest the potential pro-inflammatory role of resistin in the development of dementia, especially in dementia of vascular mechanism.
Busse M et al., 2017 [34]	60 AD patients, 20 VaD patients, 12 frontotemporal dementia patients and 24 cognitively healthy persons.	Innate and adaptive cell populations in whole blood.	Differential diagnosis	Monocytes and NK cells were diminished in VaD, but not in AD and FTD. B cell and T cell numbers were decreased in all investigated forms of dementia. Changes in the contribution of naïve/memory T cells were only present in AD.
Holm H et al., 2017 [35]	120 AD patients, 83 VaD, 102 MD and 68 other aetiology.	Plasma N-terminal prosomatostatin (NT-proSST)	Risk factor (follow-up period of 4.6 ± 1.3 years)	Higher levels of circulating NTproSST are associated with increased incidence of vascular dementia.
Holm H et al., 2017 [36]	A population-based cohort of 5347 individuals without prevalent dementia	Plasma midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal endothelin-1 (CT-proET-1) and midregional proadrenomedullin (MR-proADM).	Risk factor (follow-up period of 4.6 ± 1.3 years)	Elevated plasma concentration of MR-proANP is an independent predictor of all-cause and vascular dementia. Pronounced increase in CT-proET-1 indicates higher risk of vascular dementia.
Hsu PF et al., 2017 [37]	1436 individuals from a national representative sample in Taiwan.	CRP levels were determined.	Risk Factor (11.04 years (median) of follow-up)	260 individuals (18.11%) were diagnosed with dementia. Those with high CRP had a 55% higher risk of dementia compared with those with normal CRP. After adjusting for possible confounding cardiovascular risk factors, high CRP was independently associated with VaD, but not AD.
Moretti R et al., 2017 [38]	543 patients: 456 patients suffering from subcortical vascular dementia (sVAD), 87 AD and healthy age-matched controls	Clinical laboratory measurements, including serum total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol, have been determined enzymatically and low-density lipoprotein (LDL) cholesterol was calculated using Friedewald’s formula. Serum levels of 25(OH)D, the level of calcium and PTH were measured.The level of folate, vitamin B12 levels and Homocysteine were also tested.	Correlation	Vitamin D deficiency was present in demented cases, as well as low levels of folate and high levels of homocysteine, more pronounced in sVAD cases.
Prabhakar P et al., 2017 [39]	204 patients with small vessel VaD; 200 cognitively normal subjects.	Plasma miRNA profiling.	Differential diagnosis	plasma miR-409-3p, miR-502-3p, miR-486-5p and miR-451a could be used to differentiate small vessel VaD patients from healthy controls.
Quinlan P et al., 2017 [40]	342 patients with subjective or objective mild cognitive impairment	Serum IGF-I concentrations at baseline	Risk factor (mean follow-up: 3.6 years)	In a memory clinic population, low serum IGF-I was a risk marker for subsequent VaD whereas low IGF-I did not associate with the risk of AD. High serum IGF-I was not related to the risk of conversion to dementia.
Suridjan I et al., 2017 [41]	29 possible vascular mild cognitive impairment patients and 89 controls)	Serum lipid peroxidation markers levels. Ratios of early- (lipid hydroperoxides, LPH) to late-stage (8-isoprostane, 8-ISO; 4-hydroxy-2-nonenal, 4-HNE) lipid peroxidation products were calculated.	Correlation with cognitive status	A global effect of group on lipid peroxidation markers was observed, adjusting for sex, years of education, and cardiopulmonary fitness. Lower lipid peroxidation at baseline, as determined by lower 8-ISO concentration, was associated with greater improvement in verbal memory (F (1, 64) = 4.738, p = 0.03) and executive function (F(1, 64) = 5.219, p = 0.026) performance. Higher ratios of 8-ISO/LPH and 8-ISO+4-HNE to LPH, were associated with less improvement in executive function performance over a 24-week exercise intervention.
Tang SC et al., 2017 [42]	172 Ischemic Stroke (IS) patients, including 73 with CDR = 0, 63 with CDR = 0.5, and 36 with CDR ≥ 1 (VaD patients).	Plasma concentration of receptor for advanced glycation end products (soluble RAGE (sRAGE); endogenous soluble form of RAGE (esRAGE))	Correlation with cognitive status	Plasma sRAGE and esRAGE were elevated in patients with dementia compared with those without dementia among IS patients.
Vishnu VY et al., 2017 [43]	118 subects, 68 with dementia (MCI-AD and AD: 52; MCI VaSC and VaD:16).	Plasma IL-6; C-Reactive Protein (CRP); plasma fibrinogen; plasma D-dimer.	Differential diagnosis	Plasma Fibrinogen and D dimer: were higher in Vascular group; no difference in IL-6 and CRP.
Wang R et al.,2017 [44]	88 patients with dementia (43 AD patients, 45 VaD patients) and 45 healthy age-matched controls	Plasma Cystatin C (Cys C) and HDL levels	Differential diagnosis	Plasma Cys C levels were higher in patients with AD/VaD than in healthy subjects. Plasma HDL levels were lower in patients with AD/VaD than in healthy subjects.
Yang R et al., 2017 [45]	51 healthy subjects and 41 elderly patients (with 6 participants affected by vascular mild cognitive impairment (Va-MCI)), 9 with VaD, 8 with MCI due to AD and 18 with AD	Plasma GDF-11 and β2-MG levels	Differential diagnosis	No differences in circulating GDF-11 levels amongst the healthy advanced age and four cognitive impairment groups. β2-MG levels increased with age, but there was no significant difference between healthy elderly males and advanced age males. Increased levels of β2-MG were observed in the dementia group compared with the healthy advanced age group.
Brombo G et al., 2018 [46]	320 elderly individuals (≥65 years old): 60 patients with normal cognition; 60 patients with VaD; 100 patients with AD; 100 patients with MCI.	Plasma Klotho levels	Differential diagnosis	Lower levels of plasma Klotho (1st tertile) were associated with higher prevalence of VaD, but not AD.
Latourte A et al., 2018 [47]	1598 people.	Serum Uric Acid (SUA)	Risk Factor (median folow-up duration: 10.1 years)	Association for development of dementia was stronger with vascular or mixed dementia (HR = 3.66 (95% CI 1.29 to 10.41), p = 0.015) than Alzheimer’s disease (HR = 1.55 (95% CI 0.92 to 2.61), p = 0.10).
Lauriola M et al., 2018 [48]	116 patients: 32 healthy controls, 39 with diagnosis of VaD, 14 MCI and 31 AD.	Erythrocyte associated Aβ (iAβ40 and iAβ42) levels	Differential diagnosis	AD showed different iAβ42 levels as compared to VaD. Conversely, no differences were found for iAβ40.
Shang J et al., 2018 [49]	266 patients with AD, 44 MCI, 33 VaD and 200 ischemic stroke (IS) in comparison to 130 healthy controls.	Plasma fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)], adiponectin, reptin, plasma markers of inflammation [high-sensitivity C-reactive protein (hsCRP) and serum amyloid A (serum AA)], and plasma lipids [high-density lipoprotein and low-density lipoprotein (LDL)]	Differential disgnosis	Lower EPA and DHA levels and higher reptin and LDL levels were associated with AD and IS. The reptin/adiponectin ratio was strongly associated with IS. The hsCRP level was more strongly associated with VaD and IS, and the serum AA level was associated with all three cognitive diseases and IS.
Staszewski J et al., 2018 [50]	123 patients (age, mean ± SD: 72.2 ± 8 years, 49% females), with lacunar stroke (n = 49), vascular dementia (n = 48), and vascular parkinsonism (n = 26).	Soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble platelet selectin (sP-selectin), CD40 ligand (sCD40 L), platelet factor-4 (PF-4) and homocysteine; combined high-sensitivity C-reactive protein (hsCRP), interleukin-1α and -6 (IL-1α and IL-6, respectively) and tumor necrosis factor-α (TNF-α).	Correlation with radiological status	Lacunes are associated with different inflammatory markers.
Yang TT et al., 2018 [51]	101 MCI, 107 AD, 30 Parkinson’s disease with dementia (PDD), 20 VaD patients	Serum levels of exosomal miR-135a, -193b, and -384	Differential diagnosis	Both serum exosome miR-135a and miR-384 were up-regulated while miR-193b was down-regulated in AD patients compared with normal controls and non-AD dementias.
Staszewski et al., 2019 [52]	130 patients with marked MRI features of SVD and recent lacunar stroke (n = 52,LS), vascular Parkinsonism (n = 28,VaP) or dementia (n = 50,VaD).	IL-1α, IL-6, hs-CRP, sICAM-1, sP-selectin, TNF-α, homocysteine, fibrinogen, D-dimer, serum total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), eGFR, serum FG, HbA1c, albumin and uric acid (UA).	Risk Factor (mean follow-up time: 22.3 ± 4.3 months)	IL-1α, IL-6, homocysteine, d-dimer were significantly associated with the event of death or stroke, even after adjusting for age, sex and SVD radiological markers.