Biomarkers for Alzheimer’s Disease in Saliva: A Systematic Review

Table 1

An overview of the subjects and on the results of the included articles.

References	Biomarkers investigated	Methods used to analyze biomarkers	Number of subjects	Age of subjects	Sex of subjects	Result biomarkers
Sabbagh et al. [25]	Aβ42	ELISA	AD: Healthy controls:	Mean age; AD: Healthy controls:	Male/female; AD: 7/8; Healthy controls: 2/5	↑ Aβ42, value AD/control < 0.05
Huan et al. [14]	Metabolites	LC-MS	Two studies (discovery and validation); Discovery; AD: aMCI: Healthy controls: Validation; AD: aMCI: Healthy controls:	Two studies (discovery and validation); Discovery; Mean age; AD: 77.09; aMCI: 70.4; Healthy controls: 69.94; Validation; Mean age; AD: 70.11; aMCI: 71.5; Healthy controls: 71.4	Two studies (discovery and validation); Discovery; Male/female; AD: 6/16; aMCI: 10/15; Healthy controls: 13/22; Validation; Male/female; AD: 2/5; aMCI: 5/5; Healthy controls: 5/5	Methylguanosine, histidylphenylalanine, choline-cytidine AD/healthy controls: AUC (discovery and validation) = 1.00; Sensitivity: 100%; Specificity: 100%; value < 0.01; Amino-dihydroxybenzene,; glucosyl-galactosyl-hydroxylysine-H2O, aminobytyric acid + H2 AD/aMCI: AUC (discovery and validation) = 1.00; Sensitivity: 100%; Specificity: 100%; value < 0.01; Phenylalanylproline, phenylalanylphenylalanine, urocanic acid; AD/healthy controls: AUC discovery: 0.820; AUC validation: 0.814; Sensitivity: 71.4%; Specificity: 90.0%; value < 0.01; Alanylphenylalanine, phenylalanylproline; AD/aMCI: AUC discovery: 0.881; AUC validation: 0.786; Sensitivity: 71.4%; Specificity: 80.0%; value < 0.01
Ashton et al. [15]	t-tau	SIMOA	AD: aMCI: Healthy controls:	Mean age; AD: aMCI: Healthy controls:	Male/female; AD: 23/30; aMCI: 33/35; Healthy controls: 66/94	↑ t-tau, although not statistically significant, value AD/aMCI/healthy controls = 0.219; Correlation with ventricular volume for AD: value = 0.045
Pekeles et al. [26]	t-tau; p-tau	Western blot	Two studies (round one and round two); Round one; AD: aMCI: n=55; Healthy controls: Round two; AD: FTD: Healthy older controls: Neurological patients (other than dementia): Young healthy controls:	Two studies (round one and round two); Round one; Median age (IQR); AD: 80 (9); aMCI: 78 (14); Healthy controls: 73 (6); Round two; Median age (IQR); AD: 80 (8); FTD: 71.5 (10); Healthy older controls: 72 (7); Neurological patients (other than dementia): 55 (11); Young healthy controls: 32 (22)	Two studies (round one and round two); Round one; Male/female; AD: 24/22; aMCI: 23/32; Healthy controls: 15/32; Round two; Male/female; AD: 17/24; FTD: 11/5; Healthy older controls: 14/30; Neurological patients (other than dementia): 5/7; Young healthy controls: 31/45	Two studies (round one and round two); Round one; ↑ p-tau/t-tau at phosphorylation site: S396, S404, and the combination of S400, T403, and T404, value < 0.05; Round two; ↑ median p-tau/t-tau at phosphorylation site: S396, value AD/healthy older controls < 0.05; Sensitivity S396: 73%; Specificity S396: 50%; Sensitivity S404: 83%; Specificity S404: 30%
McGeeR et al. [13]	Aβ42	ELISA	AD: Low controls: High controls (risk for AD):	Mean age; AD: 71.3; Low controls: 54.2; High controls (risk for AD): 69	Male/female; AD: 8/5; Low controls: 17/8; High controls (risk of AD): 3/3	↑ Aβ42 (AD > high controls (risk for AD) > low controls); value AD/low controls/high controls < 0.001
Bakhtiari et al. [16]	AchE activity	Ellman’s colorimetric method	AD: Healthy controls: n=15	Mean age; AD: 78.4; Healthy controls: 71	Male/female; AD: 9/6; Healthy controls: 7/8	↑ AchE activity, value AD/control = 0.25
Carro et al. [27]	Lactoferrin	ELISA	Two studies (discovery and validation); Discovery; AD: aMCI: Healthy controls: PD: Validation; AD: aMCI: Healthy controls:	Two studies (discovery and validation); Discovery; Mean age; AD: aMCI: Healthy controls: PD: Validation; Mean age; AD: aMCI: Healthy controls:	Two studies (discovery and validation); Discovery; Male/female; AD: 31/49; aMCI: 19/25; Healthy controls: 32/59; PD: 27/32; Validation; Male/female; AD: 13/23; aMCI: 10/5; Healthy controls: 15/25	Two studies (discovery and validation); Discovery; ↓ lactoferrin, value AD/healthy controls < 0.001, value aMCI/healthy controls < 0.001; Validation; Sensitivity: 100%, specificity: 100%; Correlation with CSF Aβ42: value < 0.001; Correlation with CSF t-tau: value < 0.001; Correlation with MMSE in AD and aMCI: value < 0.001
Yilmaz et al. [17]	Metabolites (propionate, acetone)	Proton NMR spectroscopy	AD: aMCI: Healthy controls:	Mean age; AD: aMCI: Healthy controls:	Male/female; AD: 3/6; aMCI: 3/5; Healthy controls: 4/8	↑ propionate, value AD/aMCI/healthy controls = 0.034; Regression model for propionate and acetone AD/healthy controls: AUC = 0.871; Sensitivity: 90.9 %; Specificity: 84.2%
Lee et al. [12]	Aβ42	ELISA	AD+pre-AD: Healthy controls: PD:	Mean age; AD+pre-AD: 70.1; Healthy controls+PD (control): 54.6	Male/female; AD+pre-AD: 3/7; Healthy controls+PD (control): 18/9	↑ Aβ42, value AD/control < 0.001
Liang et al. [18]	Spinganine-1-phosphate; Ornithine; Phenyllactic acid; Inosine; 3-dehydrocarnitine; Hypoxanthine	FUPLC-MS	AD: n=256; Healthy controls:	Mean age; AD: Healthy controls:	Male/female; AD: 124/132; Healthy controls: 102/116	↑ spinganine-1-phosphate, value < 0.01; Sensitivity: 99.4%; Specificity: 98.2%; ↑ ornithine, value < 0.01; Sensitivity: 81.9%; Specificity: 90.7%; ↑ phenyllactic acid, value < 0.01; ↓ inosine, value < 0.01; ↓ 3-dehydrocarnitine, value < 0.01; ↓ hypoxanthine, value < 0.01
Lau et al. [19]	Trehalose; Aβ42; t-tau; p-tau	Trehalose: EG-IDFET biosensor; Aβ42, t-tau, p-tau: ELISA	AD: Healthy controls: PD:	Mean age; AD: Healthy controls: PD:	Male/female; AD: 8/12; Healthy controls: 9/11; PD: 5/15	Trehalose concentration: controls; Aβ42: not detected; t-tau: no significant differences; ↑ p-tau
Kim et al. [21]	Aβ42; Aβ40	Immunoassay with nanobeads	AD: Healthy controls:	N.A.	N.A.	↑ Aβ42 (statistically significant); ↑ Aβ40 (not statistically significant)
Shi et al. [24]	Aβ42; t-tau; p-tau	ELISA (Luminex assay)	AD: Healthy controls:	Mean age; AD: 68.8; Healthy controls: 69	Male/female; AD: 10/11; Healthy controls: 19/19	Aβ42: not detected; ↑ t-tau; ↑ p-tau; ↑ p-tau/t-tau in AD patients, value < 0.05
Bermejo-Pareja et al. [20]	Aβ42; Aβ40	ELISA	AD: (mild: , moderate: , severe: ); Healthy controls: PD:	Mean age; AD: 77.2 (60-91); Healthy controls: 74.35 (64-85); PD: 72.96 (60-93)	Male/female; AD: 21/49; Healthy controls: 17/39; PD: 26/25	Aβ42: ↑ concentration in mild and moderate AD; value mild AD = 0.043; value AD/healthy control < 0.05; Sensitivity: 16%; Specificity: 93%; Interaction with age: value = 0.016; Interaction with gender: value = 0.002; Aβ40: ↑ concentration in AD and PD
Boston et al. [22]	AchE	Ellman’s colorimetric method	AD: Healthy controls: VaD:	Mean age; AD: 83.5 (71.3-95.8); Healthy controls: 80.8 (70.8-92.1); VaD: 81.8 (71.3-93.3)	Male/female; AD: 5/10; Healthy controls: 7/6; VaD: 9/4	No significant difference
Sayer et al. [23]	AchE activity	Ellman’s colorimetric method	AD responders: AD nonresponders: 14; Healthy controls:	Mean age; AD responders: 75 (60-86); AD nonresponders: 75 (65-87); Healthy controls: 71 (64-91)	Male/female; AD responders: 7/15; AD nonresponders: 4/10; Healthy controls: 6/5	↓ AchE activity, value nonresponders/healthy controls < 0.005; Interaction with age in controls: value < 0.001

AD: Alzheimer’s disease. aMCI: amnestic mild cognitive impairment. PD: Parkinson disease. FTD: frontotemporal dementia. Aβ42: amyloid beta 1-42. Aβ40: amyloid beta 1-40. p-tau: phosphorylated tau. t-tau: total tau. AchE: acetylcholinesterase. CSF: cerebrospinal fluid. MMSE: minimental state examination. ELISA: enzyme-linked immunosorbent assay. SIMOA: single molecule array. LC-MS: liquid chromatography mass spectrometry. FUPLC-MS: fast ultraperformance liquid chromatography mass spectrometry. EG-IDFET biosensor: extended gate ion-sensitive field-effect transistor biosensor. ↑: increased levels of the biomarker in patients with AD. ↓: decreased levels of the biomarker in patients with AD. AUC: area under the curve. N.A.: not available.