{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:45:28Z","timestamp":1790999128928,"version":"4.1.0"},"reference-count":125,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82301091"],"award-info":[{"award-number":["82301091"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is characterized by progressive cognition and behavior impairments. Diagnosing AD early is important for clinicians to slow down AD progression and preserve brain function. Biomarkers such as tau protein and amyloid-\u03b2 peptide (A\u03b2) are used to aid diagnosis as clinical diagnosis often lags. Additionally, biomarkers can be used to monitor AD status and evaluate AD treatment. Clinicians detect these AD biomarkers in the brain using positron emission tomography\/computed tomography or in the cerebrospinal fluid using a lumbar puncture. However, these methods are expensive and invasive. In contrast, saliva collection is simple, inexpensive, non-invasive, stress-free, and repeatable. Moreover, damage to the brain parenchyma can impact the oral cavity and some pathogenic molecules could travel back and forth from the brain to the mouth. This has prompted researchers to explore biomarkers in the saliva. Therefore, this study provides an overview of the main finding of salivary biomarkers for AD diagnosis. Based on these available studies, A\u03b2, tau, cholinesterase enzyme activity, lactoferrin, melatonin, cortisol, proteomics, metabolomics, exosomes, and the microbiome were changed in AD patients\u2019 saliva when compared to controls. However, well-designed studies are essential to confirm the reliability and validity of these biomarkers in diagnosing and monitoring AD.<\/jats:p>","DOI":"10.3390\/ijms26052059","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T11:22:12Z","timestamp":1740568932000},"page":"2059","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["An Update of Salivary Biomarkers for the Diagnosis of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"given":"Haiying","family":"Guo","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruihuan","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weigao","family":"Cheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiwen","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5043-9981","authenticated-orcid":false,"given":"Minquan","family":"Du","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Holtzman, D.M., Morris, J.C., and Goate, A.M. (2011). Alzheimer\u2019s disease: The challenge of the second century. Sci. Transl. Med., 3.","DOI":"10.1126\/scitranslmed.3002369"},{"key":"ref_2","unstructured":"World Health Organization (2024, August 07). The Top 10 Causes of Death. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/the-top-10-causes-of-death."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2018). 2018 Alzheimer\u2019s Disease Facts and Figures. Alzheimer\u2019s Dement., 14, 367\u2013429.","DOI":"10.1016\/j.jalz.2018.02.001"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2019). 2019 Alzheimer\u2019s disease facts and figures. Alzheimer\u2019s Dement., 15, 321\u2013387.","DOI":"10.1016\/j.jalz.2019.01.010"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1038\/s43587-023-00410-4","article-title":"Detection and treatment of Alzheimer\u2019s disease in its preclinical stage","volume":"3","author":"Rafii","year":"2023","journal-title":"Nature Aging."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2021). 2021 Alzheimer\u2019s disease facts and figures. Alzheimer\u2019s Dement., 17, 327\u2013406.","DOI":"10.1002\/alz.12328"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2020). 2020 Alzheimer\u2019s disease facts and figures. Alzheimer\u2019s Dement., 16, 391\u2013460.","DOI":"10.1002\/alz.12068"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"371","DOI":"10.14283\/jpad.2021.23","article-title":"Diagnosis of Early Alzheimer\u2019s Disease: Clinical Practice in 2021","volume":"8","author":"Porsteinsson","year":"2021","journal-title":"J. Prev. Alzheimer\u2019s Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.clinbiochem.2019.04.002","article-title":"Search for biomarkers of Alzheimer\u2019s disease: Recent insights, current challenges and future prospects","volume":"72","author":"Raboch","year":"2019","journal-title":"Clin. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gunes, S., Aizawa, Y., Sugashi, T., Sugimoto, M., and Rodrigues, P.P. (2022). Biomarkers for Alzheimer\u2019s Disease in the Current State: A Narrative Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094962"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s13311-016-0481-z","article-title":"Biomarkers for the Early Detection and Progression of Alzheimer\u2019s Disease","volume":"14","author":"Counts","year":"2017","journal-title":"Neurotherapeutics"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Balasa, A.F., Chircov, C., and Grumezescu, A.M. (2020). Body Fluid Biomarkers for Alzheimer\u2019s Disease-An Up-To-Date Overview. Biomedicines, 8.","DOI":"10.3390\/biomedicines8100421"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Aisen, P.S., Cummings, J., Jack, C.R., Morris, J.C., Sperling, R., Frolich, L., Jones, R.W., Dowsett, S.A., Matthews, B.R., and Raskin, J. (2017). On the path to 2025: Understanding the Alzheimer\u2019s disease continuum. Alzheimer\u2019s Res. Ther., 9.","DOI":"10.1186\/s13195-017-0283-5"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/978-3-319-52479-5_2","article-title":"Multiplexing Biomarker Methods, Proteomics and Considerations for Alzheimer\u2019s Disease","volume":"974","author":"Robinson","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1373\/clinchem.2010.153767","article-title":"Diagnostic potential of saliva: Current state and future applications","volume":"57","author":"Pfaffe","year":"2011","journal-title":"Clin. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Solorzano, A., Brady, M., Bhatt, N., Johnson, A., Burgess, B., Leyva, H., Puangmalai, N., Jerez, C., Wood, R., and Kayed, R. (2023). Central and peripheral tau retention modulated by an anti-tau antibody. bioRxiv.","DOI":"10.1101\/2023.08.17.553682"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Liu, Z.H., Wang, Y.J., and Bu, X.L. (2023). Alzheimer\u2019s disease: Targeting the peripheral circulation. Mol. Neurodegener., 18.","DOI":"10.1186\/s13024-023-00594-8"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ullah, R., Park, T.J., Huang, X., and Kim, M.O. (2021). Abnormal amyloid beta metabolism in systemic abnormalities and Alzheimer\u2019s pathology: Insights and therapeutic approaches from periphery. Ageing Res. Rev., 71.","DOI":"10.1016\/j.arr.2021.101451"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.2174\/1567205018666210119151952","article-title":"Salivary Abeta Secretion and Altered Oral Microbiome in Mouse Models of AD","volume":"17","author":"Floden","year":"2020","journal-title":"Curr. Alzheimer Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Olsen, I., and Singhrao, S.K. (2021). Low levels of salivary lactoferrin may affect oral dysbiosis and contribute to Alzheimer\u2019s disease: A hypothesis. Med. Hypotheses, 146.","DOI":"10.1016\/j.mehy.2020.110393"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Zalewska, A., Klimiuk, A., Zi\u0119ba, S., Wnorowska, O., Rusak, M., Waszkiewicz, N., Szarmach, I., Dzier\u017canowski, K., and Maciejczyk, M. (2021). Salivary gland dysfunction and salivary redox imbalance in patients with Alzheimer\u2019s disease. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-03456-9"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Paraskevaidi, M., Allsop, D., Karim, S., Martin, F.L., and Crean, S. (2020). Diagnostic Biomarkers for Alzheimer\u2019s Disease Using Non-Invasive Specimens. J. Clin. Med., 9.","DOI":"10.3390\/jcm9061673"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3061","DOI":"10.1007\/s00784-018-2396-z","article-title":"Oral health in Alzheimer\u2019s disease: A multicenter case-control study","volume":"22","author":"Montero","year":"2018","journal-title":"Clin. Oral. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s00784-016-1923-z","article-title":"Correlation of cognitive and masticatory function in Alzheimer\u2019s disease","volume":"21","author":"Campos","year":"2017","journal-title":"Clin. Oral. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/j.jdent.2018.08.010","article-title":"The role of natural salivary defences in maintaining a healthy oral microbiota","volume":"80","year":"2019","journal-title":"J. Dent."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/prd.12393","article-title":"The oral microbiome: Role of key organisms and complex networks in oral health and disease","volume":"87","author":"Sedghi","year":"2021","journal-title":"Periodontol. 2000"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gao, S.S., Chu, C.H., and Young, F.Y.F. (2020). Oral Health and Care for Elderly People with Alzheimer\u2019s Disease. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17165713"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1007\/s40266-016-0386-x","article-title":"Prevalence of Drug-Induced Xerostomia in Older Adults with Cognitive Impairment or Dementia: An Observational Study","volume":"33","author":"Barrios","year":"2016","journal-title":"Drugs Aging"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zheng, H., and Koo, E.H. (2011). Biology and pathophysiology of the amyloid precursor protein. Mol. Neurodegener., 6.","DOI":"10.1186\/1750-1326-6-27"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.cell.2019.09.001","article-title":"Alzheimer Disease: An Update on Pathobiology and Treatment Strategies","volume":"179","author":"Long","year":"2019","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Guo, T., Zhang, D., Zeng, Y., Huang, T.Y., Xu, H., and Zhao, Y. (2020). Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer\u2019s disease. Mol. Neurodegener., 15.","DOI":"10.1186\/s13024-020-00391-7"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zhao, J., Liu, X., Xia, W., Zhang, Y., and Wang, C. (2020). Targeting Amyloidogenic Processing of APP in Alzheimer\u2019s Disease. Front. Mol. Neurosci., 13.","DOI":"10.3389\/fnmol.2020.00137"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1002\/psc.2789","article-title":"Abeta42 and Abeta40: Similarities and differences","volume":"21","author":"Qiu","year":"2015","journal-title":"J. Pept. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-019-0299-y","article-title":"Diagnosis of Alzheimer\u2019s disease utilizing amyloid and tau as fluid biomarkers","volume":"51","author":"Lee","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_35","first-page":"208","article-title":"Distribution of antiepileptic drugs between plasma, plasma water, cerebrospinal fluid, saliva and brain","volume":"5","author":"Scherber","year":"1980","journal-title":"Monogr. Neural. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Sabbagh, M.N., Shi, J., Lee, M., Arnold, L., Al-Hasan, Y., Heim, J., and McGeer, P. (2018). Salivary beta amyloid protein levels are detectable and differentiate patients with Alzheimer\u2019s disease dementia from normal controls: Preliminary findings. BMC Neurol., 18.","DOI":"10.1186\/s12883-018-1160-y"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.3233\/JAD-160748","article-title":"A Method for Diagnosing Alzheimer\u2019s Disease Based on Salivary Amyloid-beta Protein 42 Levels","volume":"55","author":"Lee","year":"2017","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Boschi, S., Roveta, F., Grassini, A., Marcinn\u00f2, A., Cermelli, A., Ferrandes, F., Rainero, I., and Rubino, E. (2022). A\u03b242 as a Biomarker of Alzheimer\u2019s Disease: Is Saliva a Viable Alternative to Cerebrospinal Fluid?. Brain. Sci., 12.","DOI":"10.3390\/brainsci12121729"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Cui, Y., Zhang, H., Zhu, J., Liao, Z., Wang, S., and Liu, W. (2022). Investigation of Whole and Glandular Saliva as a Biomarker for Alzheimer\u2019s Disease Diagnosis. Brain Sci., 12.","DOI":"10.3390\/brainsci12050595"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"McGeer, P.L., Lee, M., Kennedy, K., and McGeer, E.G. (2020). Saliva Diagnosis as a Disease Predictor. J. Clin. Med., 9.","DOI":"10.3390\/jcm9020377"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kim, C.B., Choi, Y.Y., Song, W.K., and Song, K.B. (2014). Antibody-based magnetic nanoparticle immunoassay for quantification of Alzheimer\u2019s disease pathogenic factor. J. Biomed. Opt., 19.","DOI":"10.1117\/1.JBO.19.5.051205"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.ibneur.2023.03.004","article-title":"Salivary levels of disease-related biomarkers in the early stages of Parkinson\u2019s and Alzheimer\u2019s disease: A cross-sectional study","volume":"14","author":"Sabaei","year":"2023","journal-title":"IBRO Neurosci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Bermejo-Pareja, F., Antequera, D., Vargas, T., Molina, J.A., and Carro, E. (2010). Saliva levels of Abeta1-42 as potential biomarker of Alzheimer\u2019s disease: A pilot study. BMC Neurol., 10.","DOI":"10.1186\/1471-2377-10-108"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Katsipis, G., Tzekaki, E.E., Tsolaki, M., and Pantazaki, A.A. (2021). Salivary GFAP as a potential biomarker for diagnosis of mild cognitive impairment and Alzheimer\u2019s disease and its correlation with neuroinflammation and apoptosis. J. Neuroimmunol., 361.","DOI":"10.1016\/j.jneuroim.2021.577744"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3437","DOI":"10.1007\/s00784-020-03214-7","article-title":"Salivary biomarkers in Alzheimer\u2019s disease","volume":"24","author":"Tvarijonaviciute","year":"2020","journal-title":"Clin. Oral Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"299","DOI":"10.3233\/JAD-2011-110731","article-title":"Salivary tau species are potential biomarkers of Alzheimer\u2019s disease","volume":"27","author":"Shi","year":"2011","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Lau, H.C., Lee, I.K., Ko, P.W., Lee, H.W., Huh, J.S., Cho, W.J., and Lim, J.O. (2015). Non-invasive screening for Alzheimer\u2019s 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, 10.","DOI":"10.1371\/journal.pone.0117810"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Marksteiner, J., Defrancesco, M., and Humpel, C. (2022). Saliva tau and phospho-tau-181 measured by Lumipulse in patients with Alzheimer\u2019s disease. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.1014305"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"283","DOI":"10.2174\/1567205014666170417111859","article-title":"Tau in Alzheimer\u2019s Disease: Mechanisms and Therapeutic Strategies","volume":"15","author":"Gao","year":"2018","journal-title":"Curr. Alzheimer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"656","DOI":"10.2174\/156720510793611592","article-title":"Tau in Alzheimer disease and related tauopathies","volume":"7","author":"Iqbal","year":"2010","journal-title":"Curr. Alzheimer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"56","DOI":"10.2174\/1567205015666181022094924","article-title":"Current State of Saliva Biomarkers for Aging and Alzheimer\u2019s Disease","volume":"16","author":"Francois","year":"2019","journal-title":"Curr. Alzheimer Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1007\/s12640-018-9895-1","article-title":"Clearance of Amyloid Beta and Tau in Alzheimer\u2019s Disease: From Mechanisms to Therapy","volume":"34","author":"Xin","year":"2018","journal-title":"Neurotox. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.neurobiolaging.2018.06.014","article-title":"No association of salivary total tau concentration with Alzheimer\u2019s disease","volume":"70","author":"Ashton","year":"2018","journal-title":"Neurobiol. Aging"},{"key":"ref_54","first-page":"53","article-title":"Development and validation of a salivary tau biomarker in Alzheimer\u2019s disease","volume":"11","author":"Pekeles","year":"2019","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Yuan, A., and Nixon, R.A. (2021). Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.689938"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Dhiman, K., Gupta, V.B., Villemagne, V.L., Eratne, D., Graham, P.L., Fowler, C., Bourgeat, P., Li, Q.X., Collins, S., and Bush, A.I. (2020). Cerebrospinal fluid neurofilament light concentration predicts brain atrophy and cognition in Alzheimer\u2019s disease. Alzheimer\u2019s Dement., 12.","DOI":"10.1002\/dad2.12005"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Sahrai, H., Norouzi, A., Hamzehzadeh, S., Majdi, A., Kahfi-Ghaneh, R., and Sadigh-Eteghad, S. (2023). SIMOA-based analysis of plasma NFL levels in MCI and AD patients: A systematic review and meta-analysis. BMC Neurol., 23.","DOI":"10.1186\/s12883-023-03377-2"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Gleerup, H.S., Sanna, F., H\u00f8gh, P., Simr\u00e9n, J., Blennow, K., Zetterberg, H., Hasselbalch, S.G., Ashton, N.J., and Simonsen, A.H. (2021). Saliva Neurofilament Light Chain Is Not a Diagnostic Biomarker for Neurodegeneration in a Mixed Memory Clinic Population. Front. Aging Neurosci., 13.","DOI":"10.3389\/fnagi.2021.659898"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Shim, K.H., Kang, M.J., Youn, Y.C., An, S.S.A., and Kim, S. (2022). Alpha-synuclein: A pathological factor with A\u03b2 and tau and biomarker in Alzheimer\u2019s disease. Alzheimer\u2019s Res. Ther., 14.","DOI":"10.1186\/s13195-022-01150-0"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1007\/s00401-013-1148-z","article-title":"CSF \u03b1-synuclein improves diagnostic and prognostic performance of CSF tau and A\u03b2 in Alzheimer\u2019s disease","volume":"126","author":"Toledo","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1007\/s13311-018-0628-1","article-title":"Pigment Epithelium-Derived Factor Plays a Role in Alzheimer\u2019s Disease by Negatively Regulating A\u03b242","volume":"15","author":"Huang","year":"2018","journal-title":"Neurotherapeutics"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Marucci, G., Buccioni, M., Ben, D.D., Lambertucci, C., Volpini, R., and Amenta, F. (2021). Efficacy of acetylcholinesterase inhibitors in Alzheimer\u2019s disease. Neuropharmacology, 190.","DOI":"10.1016\/j.neuropharm.2020.108352"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.clinbiochem.2003.10.007","article-title":"Association of a salivary acetylcholinesterase with Alzheimer\u2019s disease and response to cholinesterase inhibitors","volume":"37","author":"Sayer","year":"2004","journal-title":"Clin. Biochem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/scd.12342","article-title":"Evaluation of salivary acetylcholinesterase and pseudocholinesterase in patients with Alzheimer\u2019s disease: A case-control study","volume":"39","author":"Goodarzi","year":"2019","journal-title":"Spec. Care Dent."},{"key":"ref_65","first-page":"Zc58","article-title":"Can Salivary Acetylcholinesterase be a Diagnostic Biomarker for Alzheimer?","volume":"11","author":"Bakhtiari","year":"2017","journal-title":"J. Clin. Diagn. Res. JCDR"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1002\/gps.1882","article-title":"Developing a simple laboratory test for Alzheimer\u2019s disease: Measuring acetylcholinesterase in saliva\u2014A pilot study","volume":"23","author":"Boston","year":"2008","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/s41582-020-00435-y","article-title":"Neuroinflammation and microglial activation in Alzheimer disease: Where do we go from here?","volume":"17","author":"Leng","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"708","DOI":"10.4103\/1673-5374.353484","article-title":"Targeting neuroinflammation in Alzheimer\u2019s disease: From mechanisms to clinical applications","volume":"18","author":"Si","year":"2023","journal-title":"Neural Regen. Res."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"McNicholas, K., Fran\u00e7ois, M., Liu, J.W., Doecke, J.D., Hecker, J., Faunt, J., Maddison, J., Johns, S., Pukala, T.L., and Rush, R.A. (2022). Salivary inflammatory biomarkers are predictive of mild cognitive impairment and Alzheimer\u2019s disease in a feasibility study. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.1019296"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Ganne, A., Balasubramaniam, M., Griffin, W.S.T., Shmookler Reis, R.J., and Ayyadevara, S. (2022). Glial Fibrillary Acidic Protein: A Biomarker and Drug Target for Alzheimer\u2019s Disease. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14071354"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1080\/10408398.2017.1381583","article-title":"Lactoferrin: Structure, function, denaturation and digestion","volume":"59","author":"Wang","year":"2019","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"970","DOI":"10.3168\/jds.2007-0689","article-title":"Factors affecting the lactoferrin concentration in bovine milk","volume":"91","author":"Cheng","year":"2008","journal-title":"J. Dairy Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2588","DOI":"10.1007\/s00018-005-5373-z","article-title":"Lactoferricin: A lactoferrin-derived peptide with antimicrobial, antiviral, antitumor and immunological properties","volume":"62","author":"Gifford","year":"2005","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/fsn3.388","article-title":"A nutritional supplement containing lactoferrin stimulates the immune system, extends lifespan, and reduces amyloid beta peptide toxicity in Caenorhabditis elegans","volume":"5","author":"Martorell","year":"2017","journal-title":"Food Sci. Nutr."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.neulet.2010.06.079","article-title":"Deposition of lactoferrin in fibrillar-type senile plaques in the brains of transgenic mouse models of Alzheimer\u2019s disease","volume":"481","author":"Wang","year":"2010","journal-title":"Neurosci. Lett."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1080\/19390211.2021.1922567","article-title":"Lactoferrin for Mental Health: Neuro-Redox Regulation and Neuroprotective Effects across the Blood-Brain Barrier with Special Reference to Neuro-COVID-19","volume":"20","author":"Naidu","year":"2021","journal-title":"J. Diet. Suppl."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Antequera, D., Moneo, D., Carrero, L., Bartolome, F., Ferrer, I., Proctor, G., and Carro, E. (2021). Salivary Lactoferrin Expression in a Mouse Model of Alzheimer\u2019s Disease. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.749468"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1002\/alz.12107","article-title":"Salivary lactoferrin as biomarker for Alzheimer\u2019s disease: Brain-immunity interactions","volume":"16","author":"Bartolome","year":"2020","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"5516","DOI":"10.1038\/s41380-021-01248-1","article-title":"The acute phase protein lactoferrin is a key feature of Alzheimer\u2019s disease and predictor of Abeta burden through induction of APP amyloidogenic processing","volume":"26","author":"Tsatsanis","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_80","first-page":"131","article-title":"Early diagnosis of mild cognitive impairment and Alzheimer\u2019s disease based on salivary lactoferrin","volume":"8","author":"Carro","year":"2017","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Gonzalez-Sanchez, M., Bartolome, F., Antequera, D., Puertas-Martin, V., Gonzalez, P., Gomez-Grande, A., Llamas-Velasco, S., Herrero-San Martin, A., Perez-Martinez, D., and Villarejo-Galende, A. (2020). Decreased salivary lactoferrin levels are specific to Alzheimer\u2019s disease. EBioMedicine, 57.","DOI":"10.1016\/j.ebiom.2020.102834"},{"key":"ref_82","first-page":"945","article-title":"Reduced Salivary Lactoferrin Levels in Early-Onset Alzheimer\u2019s Disease","volume":"15","author":"Antequera","year":"2024","journal-title":"Aging Dis."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Gleerup, H.S., Jensen, C.S., Hogh, P., Hasselbalch, S.G., and Simonsen, A.H. (2021). Lactoferrin in cerebrospinal fluid and saliva is not a diagnostic biomarker for Alzheimer\u2019s disease in a mixed memory clinic population. EBioMedicine, 67.","DOI":"10.1016\/j.ebiom.2021.103361"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e96","DOI":"10.1016\/S2666-7568(20)30015-5","article-title":"Circadian disturbances in Alzheimer\u2019s disease progression: A prospective observational cohort study of community-based older adults","volume":"1","author":"Li","year":"2020","journal-title":"Lancet Healthy Longev."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1034\/j.1600-079X.2003.00065.x","article-title":"Early neuropathological Alzheimer\u2019s changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels","volume":"35","author":"Zhou","year":"2003","journal-title":"J. Pineal Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.phrs.2018.06.011","article-title":"Protective roles of melatonin against the amyloid-dependent development of Alzheimer\u2019s disease: A critical review","volume":"134","author":"Vincent","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.sleep.2019.04.018","article-title":"Evening melatonin timing secretion in real life conditions in patients with Alzheimer disease of mild to moderate severity","volume":"63","author":"Manni","year":"2019","journal-title":"Sleep Med."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Weissova, K., Bartos, A., Sladek, M., Novakova, M., and Sumova, A. (2016). Moderate Changes in the Circadian System of Alzheimer\u2019s Disease Patients Detected in Their Home Environment. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0146200"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Ouanes, S., and Popp, J. (2019). High Cortisol and the Risk of Dementia and Alzheimer\u2019s Disease: A Review of the Literature. Front. Aging Neurosci., 11.","DOI":"10.3389\/fnagi.2019.00043"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Ouanes, S., Clark, C., Richiardi, J., Marechal, B., Lewczuk, P., Kornhuber, J., Kirschbaum, C., and Popp, J. (2022). Cerebrospinal Fluid Cortisol and Dehydroepiandrosterone Sulfate, Alzheimer\u2019s Disease Pathology, and Cognitive Decline. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.892754"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1002\/jnr.1219","article-title":"Altered circadian cortisol secretion in Alzheimer\u2019s disease: Clinical and neuroradiological aspects","volume":"66","author":"Giubilei","year":"2001","journal-title":"J. Neurosci. Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1080\/13825585.2019.1645809","article-title":"Psychosocial stress associated with memory performance in older South African adults","volume":"27","author":"James","year":"2019","journal-title":"Aging Neuropsychol. Cogn."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.exger.2019.05.007","article-title":"Neuropsychological assessment and cortisol levels in biofluids from early Alzheimer\u2019s disease patients","volume":"123","author":"Baquero","year":"2019","journal-title":"Exp. Gerontol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.neurobiolaging.2021.07.014","article-title":"Emerging roles of oxidative stress in brain aging and Alzheimer\u2019s disease","volume":"107","author":"Cotman","year":"2021","journal-title":"Neurobiol. Aging"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Wang, Y., Xiao, T., Zhao, C., and Li, G. (2023). The Regulation of Exosome Generation and Function in Physiological and Pathological Processes. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010255"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3921","DOI":"10.2147\/JIR.S466821","article-title":"Unveiling the Complex Role of Exosomes in Alzheimer\u2019s Disease","volume":"17","author":"Sun","year":"2024","journal-title":"J. Inflamm. Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40035-023-00339-z","article-title":"Employing nanoparticle tracking analysis of salivary neuronal exosomes for early detection of neurodegenerative diseases","volume":"12","author":"Sharma","year":"2023","journal-title":"Transl. Neurodegener."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Cui, L., Zheng, J., Lu, Y., Lin, P., Lin, Y., Zheng, Y., Xu, R., Mai, Z., Guo, B., and Zhao, X. (2024). New frontiers in salivary extracellular vesicles: Transforming diagnostics, monitoring, and therapeutics in oral and systemic diseases. J. Nanobiotechnol., 22.","DOI":"10.1186\/s12951-024-02443-2"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Rani, K., Rastogi, S., Vishwakarma, P., Bharti, P.S., Sharma, V., Renu, K., Modi, G.P., Vishnu, V.Y., Chatterjee, P., and Dey, A.B. (2021). A novel approach to correlate the salivary exosomes and their protein cargo in the progression of cognitive impairment into Alzheimer\u2019s disease. J. Neurosci. Methods, 347.","DOI":"10.1016\/j.jneumeth.2020.108980"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Ryu, I.S., Kim, D.H., Ro, J.Y., Park, B.G., Kim, S.H., Im, J.Y., Lee, J.Y., Yoon, S.J., Kang, H., and Iwatsubo, T. (2023). The microRNA-485-3p concentration in salivary exosome-enriched extracellular vesicles is related to amyloid \u03b2 deposition in the brain of patients with Alzheimer\u2019s disease. Clin. Biochem., 118.","DOI":"10.1016\/j.clinbiochem.2023.110603"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"31","DOI":"10.3233\/ADR-210056","article-title":"Salivary Proteomics Identifies Transthyretin as a Biomarker of Early Dementia Conversion","volume":"6","author":"Eldem","year":"2022","journal-title":"J. Alzheimer\u2019s Dis. Rep."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.3233\/JAD-210283","article-title":"Salivaomics as a Potential Tool for Predicting Alzheimer\u2019s Disease During the Early Stages of Neurodegeneration","volume":"82","author":"Karpe","year":"2021","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Contini, C., Olianas, A., Serrao, S., Deriu, C., Iavarone, F., Boroumand, M., Bizzarro, A., Lauria, A., Faa, G., and Castagnola, M. (2021). Top-Down Proteomics of Human Saliva Highlights Anti-inflammatory, Antioxidant, and Antimicrobial Defense Responses in Alzheimer Disease. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.743596"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Contini, C., Serrao, S., Manconi, B., Olianas, A., Iavarone, F., Guadalupi, G., Messana, I., Castagnola, M., Masullo, C., and Bizzarro, A. (2023). Characterization of Cystatin B Interactome in Saliva from Healthy Elderly and Alzheimer\u2019s Disease Patients. Life, 13.","DOI":"10.3390\/life13030748"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1007\/s11306-015-0840-5","article-title":"The human saliva metabolome","volume":"11","author":"Dame","year":"2015","journal-title":"Metabolomics"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"583","DOI":"10.3233\/JAD-181278","article-title":"Acyl-Alkyl-Phosphatidlycholines are Decreased in Saliva of Patients with Alzheimer\u2019s Disease as Identified by Targeted Metabolomics","volume":"68","author":"Marksteiner","year":"2019","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"355","DOI":"10.3233\/JAD-161226","article-title":"Diagnostic Biomarkers of Alzheimer\u2019s Disease as Identified in Saliva using 1H NMR-Based Metabolomics","volume":"58","author":"Yilmaz","year":"2017","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.3233\/JAD-180711","article-title":"Metabolomics Analyses of Saliva Detect Novel Biomarkers of Alzheimer\u2019s Disease","volume":"65","author":"Huan","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"96074","DOI":"10.1039\/C5RA19094K","article-title":"Metabolomics-based screening of salivary biomarkers for early diagnosis of Alzheimer\u2019s disease","volume":"5","author":"Liang","year":"2015","journal-title":"RSC Adv."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Sapkota, S., Huan, T., Tran, T., Zheng, J., Camicioli, R., Li, L., and Dixon, R.A. (2018). Alzheimer\u2019s Biomarkers From Multiple Modalities Selectively Discriminate Clinical Status: Relative Importance of Salivary Metabolomics Panels, Genetic, Lifestyle, Cognitive, Functional Health and Demographic Risk Markers. Front. Aging Neurosci., 10.","DOI":"10.3389\/fnagi.2018.00296"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1111\/odi.14110","article-title":"Profiling the oral microbiomes in patients with Alzheimer\u2019s disease","volume":"29","author":"Guo","year":"2021","journal-title":"Oral Dis."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"633","DOI":"10.3233\/JAD-190587","article-title":"Analysis of Salivary Microbiome in Patients with Alzheimer\u2019s Disease","volume":"72","author":"Liu","year":"2019","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"3677","DOI":"10.1111\/odi.14348","article-title":"Oral microbiome and serological analyses on association of Alzheimer\u2019s disease and periodontitis","volume":"29","author":"Fu","year":"2022","journal-title":"Oral Dis."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Bathini, P., Foucras, S., Dupanloup, I., Imeri, H., Perna, A., Berruex, J.L., Doucey, M.A., Annoni, J.M., and Auber Alberi, L. (2020). Classifying dementia progression using microbial profiling of saliva. Alzheimer\u2019s Dement., 12.","DOI":"10.1002\/dad2.12000"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/S1474-4422(21)00066-1","article-title":"Clinical diagnosis of Alzheimer\u2019s disease: Recommendations of the International Working Group","volume":"20","author":"Dubois","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"34","DOI":"10.14744\/DAJPNS.2024.00235","article-title":"The relationship between the diagnostic value of salivary cortisol levels and behavioral symptoms in patients with Alzheimer\u2019s disease","volume":"37","author":"Bozyel","year":"2024","journal-title":"Dusunen Adam J. Psychiatry Neurol. Sci."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"545","DOI":"10.2147\/JPR.S176857","article-title":"Melatonin is a biomarker of circadian dysregulation and is correlated with major depression and fibromyalgia symptom severity","volume":"12","author":"Caumo","year":"2019","journal-title":"J. Pain Res."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"209","DOI":"10.5483\/BMBRep.2015.48.4.275","article-title":"Technical and clinical aspects of cortisol as a biochemical marker of chronic stress","volume":"48","author":"Lee","year":"2015","journal-title":"BMB Rep."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Calabresi, P., Mechelli, A., Natale, G., Volpicelli-Daley, L., Di Lazzaro, G., and Ghiglieri, V. (2023). Alpha-synuclein in Parkinson\u2019s disease and other synucleinopathies: From overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis., 14.","DOI":"10.1038\/s41419-023-05672-9"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1111\/jcpe.13267","article-title":"Periodontitis and systemic markers of neurodegeneration: A case-control study","volume":"47","author":"Leira","year":"2020","journal-title":"J. Clin. Periodontol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1016\/j.molimm.2006.09.003","article-title":"Cleaved inflammatory lactoferrin peptides in parotid saliva of periodontitis patients","volume":"44","author":"Komine","year":"2007","journal-title":"Mol. Immunol."},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Ji, S., Kook, J.K., Park, S.N., Lim, Y.K., Choi, G.H., and Jung, J.S. (2023). Characteristics of the Salivary Microbiota in Periodontal Diseases and Potential Roles of Individual Bacterial Species To Predict the Severity of Periodontal Disease. Microbiol. Spectr., 11.","DOI":"10.1128\/spectrum.04327-22"},{"key":"ref_123","first-page":"1574","article-title":"Lactotransferrin immunocytochemistry in Alzheimer and normal human brain","volume":"142","author":"Kawamata","year":"1993","journal-title":"Am. J. Pathol."},{"key":"ref_124","first-page":"10","article-title":"Lactoferrin and oral diseases: Current status and perspective in periodontitis","volume":"2","author":"Berlutti","year":"2011","journal-title":"Ann. Stomatol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.jim.2005.09.010","article-title":"Impact of saliva collection methods on sIgA and cortisol assays and acceptability to participants","volume":"307","author":"Strazdins","year":"2005","journal-title":"J. Immunol. 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