Salivary Proteomics Identifies Transthyretin as a Biomarker of Early Dementia Conversion.

Background: Alzheimer's disease (AD) remains to date an incurable disease with a long asymptomatic phase. Early diagnosis in peripheral biofluids has emerged as key for identifying subjects at risk and developing therapeutics and preventative approaches. Objective: We apply proteomics discovery to identify salivary diagnostic biomarkers for AD, which are suitable for self-sampling and longitudinal biomonitoring during aging. Methods: 57 participants were recruited for the study and were categorized into Cognitively normal (CNh) (n = 19), mild cognitive impaired (MCI) (n = 21), and Alzheimer's disease (AD) (n = 17). On a subset of subjects, 3 CNh and 3 mild AD, shot-gun filter aided sample preparation (FASP) proteomics and liquid chromatography mass spectroscopy (LC-MS/MS) was employed in saliva and cerebrospinal fluid (CSF) to identify neural-derived proteins. The protein level of salivary Transthyretin (TTR) was validated using western blot analysis across groups. Results: We found that 19.8% of the proteins in saliva are shared with CSF. When we compared the saliva and CSF proteome, 24 hits were decreased with only one protein expressed more. Among the differentially expressed proteins, TTR with reported function in amyloid misfolding, shows a significant drop in AD samples, confirmed by western blot showing a 0.5-fold reduction in MCI and AD compared to CNh. Conclusion: A reduction in salivary TTR appears with the onset of cognitive symptoms. More in general, the proteomic profiling of saliva shows a plethora of biomarkers worth pursuing as non-invasive hallmarks of dementia in the preclinical stage.

Classifying dementia progression using microbial profiling of saliva.

INTRODUCTION: There is increasing evidence linking periodontal infections to Alzheimer's disease (AD). Saliva sampling can reveal information about the host and pathogen interactions that can inform about physiological and pathological brain states. METHODS: A cross-sectional cohort of age-matched participants (78) was segmented according to their chemosensory (University of Pennsylvania Smell Identification Test; UPSIT) and cognitive scores (Mini-Mental State Exam; MMSE and clinical dementia rating; CDR). Mid-morning saliva was sampled from each participant and processed for microbiome composition and cytokine analysis. Linear discriminant analysis (LDA) was used to unravel specific changes in microbial and immunological signatures and logistic regression analysis (LRA) was employed to identify taxa that varied in abundance among patient groups. RESULTS: Using olfaction we distinguish in the cognitively normal population a segment with high chemosensory scores (CNh, 27) and another segment with chemosensory scores (CNr, 16) as low as mild cognitive impairment (MCI, 21) but higher than the AD group (17). We could identify stage-specific microbial signatures changes but no clearly distinct cytokine profiles. Periodontal pathogen species as Filifactor villosus decline with the increasing severity of AD, whereas opportunistic oral bacteria such as Leptotrichia wadei show a significant enrichment in MCI. CONCLUSIONS: The salivary microbiome indicates stage-dependent changes in oral bacteria favoring opportunistic species at the expense of periodontal bacteria, whereas the inflammatory profiles remain mainly unchanged in the sampled population.