Diagnostic accuracy of salivary biomarkers in alzheimer's disease: A systematic review

Main Article Content

Amir A Majeed
Auday M Al-Anee
Natheer H Al-Rawi

Abstract

Background: Alzheimer's disease causes cognitive decline and neuronal death due to amyloid-beta plaques and neurofibrillary tangles. Current diagnostic methods are intrusive, expensive, and few, but early diagnosis improves patient outcomes. Due to its oral-brain axis relationship to the central nervous system, saliva may be a viable source of non-invasive Alzheimer's biomarkers. This systematic review aimed to assess the diagnostic potential of salivary biomarkers for Alzheimer's disease by carefully reviewing the existing data. Methodology: Studies published between January 1, 2008, and September 30, 2023, were the subject of a thorough literature search in the PubMed, Scopus, and Web of Science databases. Relevant data were extracted after studies were evaluated according to predetermined inclusion and exclusion criteria. The Oxford Centre for Evidence-Based Medicine criteria were implemented to evaluate the quality of the studies that were incorporated. Results: A total of 36 studies were included in the systematic review, as they met the inclusion criteria. Alzheimer's disease patients exhibited significantly elevated salivary levels of beta-amyloid- 42 and p-tau in comparison to healthy controls. Patients with Alzheimer's disease exhibited non-significant trends in salivary t-tau and lactoferrin. Conclusion: The levels of beta-amyloid-42 and p-tau in the saliva of patients with Alzheimer's disease are significantly altered. Beta-amyloid-42 regard as a best marker in early diagnosis by salivary sample. These findings emphasize the prospect of saliva as a non-invasive source of biomarkers for the diagnosis of Alzheimer's disease. Nevertheless, salivary tests must undergo additional validation in larger, well-characterized cohorts and standardization of methodologies before they can be implemented in clinical practice.

Downloads

Download data is not yet available.

Article Details

Section

Review Articles

Author Biographies

Amir A Majeed, Department of Oral Diagnostic Sciences, College of Dentistry, University of Baghdad, Iraq.

Department of Oral Diagnostic Sciences, College of Dentistry, University of Baghdad, Iraq.

Auday M Al-Anee, Department of Oral and Maxillofacial Surgery, College of Dentistry, University of Baghdad, Iraq.

Department of Oral and Maxillofacial Surgery, College of Dentistry, University of Baghdad, Iraq.

Natheer H Al-Rawi, Department of Oral and Craniofacial Health Sciences, University of Sharjah, UAE.

Department of Oral and Craniofacial Health Sciences, University of Sharjah, UAE.

How to Cite

1.
Majeed AA, Al-Anee AM, Al-Rawi NH. Diagnostic accuracy of salivary biomarkers in alzheimer’s disease: A systematic review. J Bagh Coll Dent [Internet]. 2025 Dec. 15 [cited 2025 Dec. 16];37(4):80-98. Available from: https://jbcd.uobaghdad.edu.iq/index.php/jbcd/article/view/4098

References

Guo T, Zhang D, Zeng Y, Huang TY, Xu H, Zhao Y. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Mol Neurodegener. 2020;15(1):40.

Zhang XX, Tian Y, Wang ZT, Ma YH, Tan L, Yu JT. The epidemiology of Alzheimer’s disease modifiable risk factors and prevention. J Prev Alzheimers Dis. 2021;8(3):313–21.

Porsteinsson AP, Isaacson RS, Knox S, Sabbagh MN, Rubino I. Diagnosis of early Alzheimer’s disease: clinical practice in 2021. J Prev Alzheimers Dis. 2021;8(3):371–86.

Chen Z, Zhong C. Oxidative stress in Alzheimer’s disease. Neurosci Bull. 2014;30(2):271–81. .

Song T, Song X, Zhu C, Patrick R, Skurla M, Santangelo I, et al. Mitochondrial dysfunction, oxidative stress, neuroinflammation, and metabolic alterations in the progression of Alzheimer’s disease: A meta-analysis of in vivo magnetic resonance spectroscopy studies. Ageing Res Rev. 2021; 72:101503.

Lane CA, Hardy J, Schott JM. Alzheimer’s disease. Eur J Neurol. 2018;25(1):59–70.

Mendiola-Precoma J, Berumen LC, Padilla K, Garcia-Alcocer G. Therapies for prevention and treatment of Alzheimer’s disease. Biomed Res Int. 2016;2016(1):2589276.

Jack Jr CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA‐AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimer’s & dementia. 2018;14(4):535–62.

Mahaman YAR, Embaye KS, Huang F, Li L, Zhu F, Wang JZ, et al. Biomarkers used in Alzheimer’s disease diagnosis, treatment, and prevention. Ageing Res Rev. 2022; 74:101544.

Ibrahim AA, Ai-Lami F, Al-Rudainy R, Khader YS. Mental disorders among elderly people in Baghdad, Iraq, 2017. INQUIRY: The Journal of Health Care Organization, Provision, and Financing. 2019; 56.

Ashton NJ, Ide M, Zetterberg H, Blennow K. Salivary biomarkers for Alzheimer’s disease and related disorders. Neuro. and Ther. 2019 Dec; 8:83-94.

Hussein SI, Abd ST, AL-khayat FA, k Mahmood H. Complete blood count and saliva parameters as an indicator for infected patients with coronavirus COVID-19. J Bagh Coll Den. 2023;35(1):76–85.

Al-Joboury AAM, Rasheed RH. An Assessment of Oral Health in Hypertensive Patients Treated with HMG-CoA Reductase Inhibitors (Statins). J Bagh Coll Dent. 2015;27(4):85–9.

Al-Kubaisi MW, Al-Ghurabi BH, Alkubaisy W, ABDULLAH NN. Anti-inflammatory effects of manuka honey on salivary cytokines (clinical study). J Bagh Coll Dent. 2023;35(1):10–9.

Gul SS, Abdulkareem AA, Sha AM, Rawlinson A. Diagnostic accuracy of oral fluids biomarker profile to determine the current and future status of periodontal and peri-implant diseases. Diagnostics. 2020;10(10):838.

Al-Taweel FBH, Saliem SS, Abd OH, Whawell SA. Assessment of serum interleukin-1β and interleukin-6 levels in patients with chronic periodontitis and coronary heart disease. European J Gen Dent. 2021;10(02):78–83.

Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. bmj. 2021;372. .

OCEBM Levels of Evidence Working Group. The Oxford 2011Levels of Evidence. Oxford Centre for Evidence-Based Medicine. http://www.cebm.net/index.aspx?o=5653. Accessed 22 Sept 2012

Wells GASB, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle -Ottawa scale (NOS) for assessing the qualityif nonrandomized studies inmeta-analyses. 2011

Peña-Bautista C, Baquero M, Ferrer I, Hervás D, Vento M, García-Blanco A, et al. Neuropsychological assessment and cortisol levels in biofluids from early Alzheimer’s disease patients. Exp Gerontol. 2019; 123:10–6.

Carro E, Bartolomé F, Bermejo-Pareja F, Villarejo-Galende A, Molina JA, Ortiz P, et al. Early diagnosis of mild cognitive impairment and Alzheimer’s disease based on salivary lactoferrin. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. 2017; 8:131–8.

Bermejo-Pareja F, Antequera D, Vargas T, Molina JA, Carro E. Saliva levels of Abeta1-42 as potential biomarker of Alzheimer’s disease: a pilot study. BMC Neurol. 2010;10(1):108.

Santos GAA, Olave E, Pardi PC. Salivary Biomarkers in Alzheimer’s Disease. International Journal of Morphology. 2020;38(1):230-4.

Katsipis G, Tzekaki EE, Tsolaki M, Pantazaki AA. Salivary GFAP as a potential biomarker for diagnosis of mild cognitive impairment and Alzheimer’s disease and its correlation with neuroinflammation and apoptosis. J Neuroimmunol. 2021; 361:577744.

Zalewska A, Klimiuk A, Zięba S, Wnorowska O, Rusak M, Waszkiewicz N, et al. Salivary gland dysfunction and salivary redox imbalance in patients with Alzheimer’s disease. Sci Rep. 2021;11(1):23904.

Lau HC, Yu JB, Lee HW, Huh JS, Lim JO. Investigation of exhaled breath samples from patients with Alzheimer’s disease using gas chromatography-mass spectrometry and an exhaled breath sensor system. Sensors. 2017;17(8):1783. .

Lee DY, Kim E, Choi MH. Technical and clinical aspects of cortisol as a biochemical marker of chronic stress. BMB Rep. 2015;48(4):209-16.

McGeer PL, Guo JP, Lee M, Kennedy K, McGeer EG. Alzheimer’s disease can be spared by nonsteroidal anti-inflammatory drugs. J Alzheimer’s Dis. 2018;62(3):1219–22.

Pukhalskaia AE, Dyatlova AS, Linkova NS, Kozlov KL, Kvetnaia T V, Koroleva M V, et al. Sirtuins as possible predictors of aging and Alzheimer’s disease development: verification in the hippocampus and saliva. Bull Exp Biol Med. 2020;169(6):821–4.

González-Sánchez M, Bartolome F, Antequera D, Puertas-Martín V, González P, Gómez-Grande A, et al. Decreased salivary lactoferrin levels are specific to Alzheimer’s disease. EBioMedicine. 2020;57.

Gleerup HS, Jensen CS, Høgh P, Hasselbalch SG, Simonsen AH. Lactoferrin in cerebrospinal fluid and saliva is not a diagnostic biomarker for Alzheimer’s disease in a mixed memory clinic population. EBioMedicine. 2021;67.

McNicholas K, François M, Liu JW, Doecke JD, Hecker J, Faunt J, et al. Salivary inflammatory biomarkers are predictive of mild cognitive impairment and Alzheimer’s disease in a feasibility study. Front Aging Neurosci. 2022; 14:1019296.

Sabaei M, Rahimian S, Ketabforoush AHME, Rasoolijazi H, Zamani B, Hajiakhoundi F, et al. Salivary levels of disease-related biomarkers in the early stages of Parkinson’s and Alzheimer’s disease: a cross-sectional study. IBRO Neurosci Rep. 2023; 14:285–92.

Huan T, Tran T, Zheng J, Sapkota S, MacDonald SW, Camicioli R, et al. Metabolomics analyses of saliva detect novel biomarkers of Alzheimer’s disease. J Alzheimer’s Dis. 2018;65(4):1401–16.

Peña-Bautista C, Torres-Cuevas I, Baquero M, Ferrer I, García L, Vento M, et al. Early neurotransmission impairment in non-invasive Alzheimer Disease detection. Sci Rep. 2020;10(1): 16396.

Lau HC, Lee IK, Ko PW, Lee HW, Huh JS, Cho WJ, et al. Non-invasive screening for Alzheimer’s disease by sensing salivary sugar using Drosophila cells expressing gustatory receptor (Gr5a) immobilized on an extended gate ion-sensitive field-effect transistor (EG-ISFET) biosensor. PLoS One. 2015;10(2): e0117810.

Shi Y, Wang H, Zhu Z, Ye Q, Lin F, Cai G. Association between exposure to phenols and parabens and cognitive function in older adults in the United States: A cross-sectional study. Science of The Total Environment. 2023; 858:160129.

Bakhtiari S, Moghadam NB, Ehsani M, Mortazavi H, Sabour S, Bakhshi M. Can salivary acetylcholinesterase be a diagnostic biomarker for Alzheimer? J Clin Diagn Res. 2017;11(1): ZC58.

Yilmaz A, Geddes T, Han B, Bahado-Singh RO, Wilson GD, Imam K, et al. Diagnostic biomarkers of Alzheimer’s disease as identified in saliva using 1H NMR-based metabolomics. J Alzheimer’s Dis. 2017;58(2):355–9. .

Sabbagh MN, Shi J, Lee M, Arnold L, Al-Hasan Y, Heim J, et al. Salivary beta amyloid protein levels are detectable and differentiate patients with Alzheimer’s disease dementia from normal controls: Preliminary findings. BMC Neurol. 2018;18(1):155.

Tvarijonaviciute A, Zamora C, Ceron JJ, Bravo-Cantero AF, Pardo-Marin L, Valverde S, et al. Salivary biomarkers in Alzheimer’s disease. Clin Oral Investig. 2020;24(10):3437–44.

Boschi S, Roveta F, Grassini A, Marcinnò A, Cermelli A, Ferrandes F, et al. Aβ42 as a biomarker of Alzheimer’s disease: is saliva a viable alternative to cerebrospinal fluid? Brain Sci. 2022;12(12):1729.

Eldem E, Barve A, Sallin O, Foucras S, Annoni JM, Schmid AW, et al. Salivary proteomics identifies transthyretin as a biomarker of early dementia conversion. J Alzheimers Dis Rep. 2022;6(1):31–41.

Marksteiner J, Defrancesco M, Humpel C. Saliva tau and phospho-tau-181 measured by Lumipulse in patients with Alzheimer’s disease. Front Aging Neurosci. 2022; 14:1014305.

Boston PF, Gopalkaje K, Manning L, Middleton L, Loxley M. Developing a simple laboratory test for Alzheimer’s disease: measuring acetylcholinesterase in saliva‐a pilot study. International Journal of Geriatric Psychiatry: A journal of the psychiatry of late life and allied sciences. 2008;23(4):439–40.

Souza-Talarico JN de, Caramelli P, Nitrini R, Chaves EC. Effect of cortisol levels on working memory performance in elderly subjects with Alzheimer’s disease. Arq Neuropsiquiatr. 2008; 66:619–24.

Kim CB, Choi YY, Song WK, Song KB. Antibody-based magnetic nanoparticle immunoassay for quantification of Alzheimer’s disease pathogenic factor. J Biomed Opt. 2014;19(5):51205.

Liang Q, Liu H, Zhang T, Jiang Y, Xing H, Zhang A hua. Metabolomics-based screening of salivary biomarkers for early diagnosis of Alzheimer’s disease. RSC Adv. 2015;5(116):96074–9.

Ahmadi‐Motamayel F, Goodarzi MT, Tarazi S, Vahabian M. Evaluation of salivary acetylcholinesterase and pseudocholinesterase in patients with Alzheimer’s disease: A case–control study. Special Care in Dentistry. 2019;39(1):39–44.

Pekeles H, Qureshi HY, Paudel HK, Schipper HM, Gornistky M, Chertkow H. Development and validation of a salivary tau biomarker in Alzheimer’s disease. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. 2019; 11:53–60.

François M, Karpe A, Liu JW, Beale D, Hor M, Hecker J, et al. Salivaomics as a potential tool for predicting Alzheimer’s disease during the early stages of neurodegeneration. J Alzheimer’s Dis. 2021;82(3):1301–13.

Cui Y, Zhang H, Zhu J, Liao Z, Wang S, Liu W. Investigation of whole and glandular saliva as a biomarker for Alzheimer’s disease diagnosis. Brain Sci. 2022;12(5):595.

Ryu IS, Kim DH, Ro JY, Park BG, Kim SH, Im JY, et al. The microRNA-485-3p concentration in salivary exosome-enriched extracellular vesicles is related to amyloid β deposition in the brain of patients with Alzheimer’s disease. Clin Biochem. 2023; 118:110603.

Contini C, Fadda L, Lai G, Masala C, Olianas A, Castagnola M, et al. A top‐down proteomic approach reveals a salivary protein profile able to classify Parkinson’s disease with respect to Alzheimer’s disease patients and to healthy controls. Proteomics. 2024;24(3–4):2300202.

Shi M, Sui YT, Peskind ER, Li G, Hwang H, Devic I, et al. Salivary tau species are potential biomarkers of Alzheimer’s disease. J Alzheimer’s Dis. 2011;27(2):299–305.

Nijakowski K, Zdrojewski J, Nowak M, Gruszczyński D, Knoll F, Surdacka A. Salivary Metabolomics for Systemic Cancer Diagnosis: A Systematic Review. Metabolites. 2022;13(1).

Gouras GK, Olsson TT, Hansson O. β-Amyloid peptides and amyloid plaques in Alzheimer’s disease. Neurotherapeutics. 2015;12(1):3–11.

Imran NK, Ali OH, Ahmed MA. Evaluation of Salivary? -Amylase Enzyme Activity in Smoker and Peptic Ulcer Patients affected by Periodontitis in Relation to Clinical Periodontal Parameters. Indian Journal of Forensic Medicine & Toxicology. 2020;14(4):2349–55.

Yong SJ, Veerakumarasivam A, Lim WL, Chew J. Neuroprotective effects of lactoferrin in Alzheimer’s and Parkinson’s diseases: A narrative review. ACS Chem Neurosci. 2023;14(8):1342–55.

Thapa S, Lv M, Xu H. Acetylcholinesterase: a primary target for drugs and insecticides. Mini Rev Med Chem. 2017;17(17):1665–76.

Saxena M, Dubey R. Target enzyme in Alzheimer’s disease: Acetylcholinesterase inhibitors. Curr Top Med Chem. 2019;19(4):264–75.

Avila J, Lucas JJ, Perez MAR, Hernandez F. Role of tau protein in both physiological and pathological conditions. Physiol Rev. 2004.

Peineau S, Rabiant K, Pierrefiche O, Potier B. Synaptic plasticity modulation by circulating peptides and metaplasticity: Involvement in Alzheimer’s disease. Pharmacol Res. 2018; 130:385–401.

Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14(4):388–405.

Ouanes S, Popp J. High Cortisol and the Risk of Dementia and Alzheimer's Disease: A Review of the Literature. Front Aging Neurosci. 2019;11:43.

Enad HH, Al-Mizraqchi AS. Salivary Cortisol as a Stress Biomarker and Total Viable Count of Salivary Bacterial Microbiome among COVID-19 Patients. J Bagh Coll Dent. 2021;33(4):6-10.

Paula‐Lima AC, Brito‐Moreira J, Ferreira ST. Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer’s disease. J Neurochem. 2013;126(2):191–202.

Dalangin R, Kim A, Campbell RE. The role of amino acids in neurotransmission and fluorescent tools for their detection. Int J Mol Sci. 2020;21(17):6197.

Ho PTB, Clark IM, Le LTT. MicroRNA-based diagnosis and therapy. Int J Mol Sci. 2022;23(13):7167.

Carafa V, Rotili D, Forgione M, Cuomo F, Serretiello E, Hailu GS, et al. Sirtuin functions and modulation: from chemistry to the clinic. Clin Epigenetics. 2016;8(1):61.

Pukhalskaia AE, Dyatlova AS, Linkova NS, Kozlov KL, Kvetnaia T V, Koroleva M V, et al. Sirtuins as possible predictors of aging and Alzheimer’s disease development: verification in the hippocampus and saliva. Bull Exp Biol Med. 2020;169(6):821–4.

Khalifeh M, Read MI, Barreto GE, Sahebkar A. Trehalose against Alzheimer’s disease: insights into a potential therapy. BioEssays. 2020;42(8):1900195.

Johnson CH, Ivanisevic J, Siuzdak G. Metabolomics: beyond biomarkers and towards mechanisms. Nat Rev Mol Cell Biol. 2016;17(7):451–9.

Similar Articles

You may also start an advanced similarity search for this article.