Saliva phosphorylated tau concentration is not associated with Alzheimer's disease, cerebrospinal fluid or blood biomarkers

Helena Sophia Gleerup^1,2*Federica Sanna^3,4Srinivas Koutarapu^3,5Juan Lantero-Rodriguez³Laia Montoliu-Gaya³Jörg Hanrieder^3,6,7Gunnar Brinkmalm³Thomas K Karikari³Peter Høgh⁸Kaj Blennow^3,6Steen Gregers Hasselbalch^2,9Henrik Zetterberg^{10,11,12,3,6,7}Nicholas James Ashton^13,14,3Anja Hviid Simonsen²

• ¹Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
• ²Department of Neurology, Danish Dementia Research Centre (DDRC), Copenhagen University Hospital, Rigshospitalet, Inge Lehmanns Vej 8, 2100, Copenhagen, Denmark, Copenhagen, Denmark
• ³Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Wallinsgatan 6, 43139, Mölndal, Sweden, Mölndal, Sweden
• ⁴Università degli Studi di Cagliari, Via Universita 40, 09124, Cagliari, Italy, Cagliari, Italy
• ⁵Washington University School of Medicine, Department of Pathology and Immunology, 660 S Euclid Ave, St. Louis, MO, USA, St. Louis, United States
• ⁶Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden, Mölndal, Sweden
• ⁷Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom, london, United Kingdom
• ⁸Regional Dementia Research Centre, Region Zealand, Roskilde Hospital, University of Copenhagen, Vestermarksvej 11, 4000, Roskilde, Denmark., Roskilde, Denmark
• ⁹Department of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Blegdamsvej 3, 2100, Copenhagen, Denmark, Copenhagen, Denmark
• ¹⁰UK Dementia Research Institute at UCL, 338 Euston Rd., London, United Kingdom, london, United Kingdom
• ¹¹Hong Kong Centre for Neurodegenerative Diseases, InnoHK, 17 Science Park W Ave, Science Park, Hong Kong, China, Hong Kong, China
• ¹²Wisconsin Alzheimer’s Disease Research Centre, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, 600 Highland Ave, Madison, WI 53792, USA, Maddison, United States
• ¹³Banner Alzheimer's Institute and University of Arizona, 901 E Willetta St, Phoenix, AZ, USA, Phoenix, United States
• ¹⁴Banner Sun Health Research Institute, Sun City, AZ 85351, USA, Sun City, United States

Objective: One of the most challenging aims of the scientific community in the last decade, is to find an easily accessible matrix in which neurodegeneration-related biomarkers can be measured and used to diagnose Alzheimer's disease (AD) in vivo. Blood biomarkers have led the way in this regard, specifically, phosphorylated tau (p-tau) which demonstrates excellent diagnostic and prognostic properties. The recent success of the blood biomarkers for AD pathophysiology poses a new question – can p-tau be measured in other peripheral and more even more accessible biofluids, and do they have relation to disease? Saliva contains biomarkers linked to neurodegeneration and it has been proposed as a potential sample type that would be minimally invasive to collect for this purpose. Methods: In this study, we confirmed the presence of several p-tau species in saliva fluid and saliva gland tissue by Immunoprecipitation-Mass spectrometry (IP-MS) and immunohistochemistry, respectively. Furthermore, we measured saliva and plasma p-tau181 concentrations in 125 memory clinic participants, using ultrasensitive Single molecule array (Simoa) technology. Results: Despite a weak correlation between saliva p-tau181 and CSF t-tau (rho=0.13, P <0.01), there were no significant differences in saliva p-tau181 concentration between the different clinical groups and the healthy controls. Interpretation: For this reason, we conclude that saliva p-tau181 is not acceptable as a biomarker for AD.