Saliva Proteome, Metabolome and Microbiome Signatures for Detection of Alzheimer's Disease

As the burden of Alzheimer's disease (AD) escalates with an ageing population, the demand for early and accessible diagnostic methods becomes increasingly urgent. Saliva, with its non-invasive and cost-effective nature, presents a promising alternative to cerebrospinal fluid and plasma for biomarker discovery. : In this study, we conducted a comprehensive multi-omics analysis of saliva samples ( = 20 mild cognitive impairment (MCI), = 20 Alzheimer's disease and age- and = 40 gender-matched cognitively normal individuals), from the South Australian Neurodegenerative Disease (SAND) cohort, integrating proteomics, metabolomics, and microbiome data with plasma measurements, including pTau181. : Among the most promising findings, the protein Stratifin emerged as a top candidate, showing a strong negative correlation with plasma pTau181 (r = -0.49, < 0.001) and achieving an AUC of 0.95 in distinguishing AD and MCI combined from controls. In the metabolomics analysis, 3-chlorotyrosine and L-tyrosine exhibited high correlations with disease severity progression, with AUCs of 0.93 and 0.96, respectively. Pathway analysis revealed significant alterations in vitamin B12 metabolism, with Transcobalamin-1 levels decreasing in saliva as AD progressed despite an increase in serum vitamin B12 levels ( = 0.008). Microbiome analysis identified shifts in bacterial composition, with a microbiome cluster containing species such as showing a significant decrease in abundance in MCI and AD samples. The overall findings were reinforced by weighted correlation network analysis, which identified key hubs and enriched pathways associated with AD. : Collectively, these data highlight the potential of saliva as a powerful medium for early AD diagnosis, offering a practical solution for large-scale screening and monitoring.