Project Summary As our population ages, the prevalence of aging-related disorders such as cognitive decline, Alzheimer’s disease (AD), and its related dementia (ADRD) is increasing, with poor or no prognosis, prevention, and treatments. This, in turn, burdens families, society, and our healthcare system. Although, several recent advances have led to the development of prognostic markers of ADRD including advanced imaging like MRI, PET, and measurements of amyloid-β (Aβ) and tau proteins in cerebrospinal fluid (CSF) and blood; but their uses are impeded due to cost, invasiveness, and required frequency of measurements, with limitations in sensitivity and accuracy. Thus, developing new, non-invasive, sensitive, and easy to frequently measure with increased accuracy biomarkers for predicting the risk of early onset of cognitive decline and ADRD progression is direly needed. Saliva is an attractive reservoir of biomarkers that can noninvasively and inexpensively be collected with unlimited frequency. We hypothesize that saliva protein markers can differentiate mild cognitive impairment (MCI) and dementia from cognitively healthy individuals. We also posit that these saliva protein markers can predict the risk of MCI and dementia, and the inclusion of oral microbiome and systemic inflammatory markers will strengthen the discriminatory and predictive power. Our hypothesis is based on strong fundamental knowledge and preliminary data. The fact that the oral cavity’s mucosal and lymphatic systems are connected to the brain circulations and are in physical proximity, which allows the bidirectional exchange of molecules like proteins and peptides, between oral and brain systems. Abnormalities in the oral microbiome and systemic inflammation are linked to the risk of cognitive decline and ADRD, but these conclusions are drawn from small, cross-sectional, observational, and non-prospective risk prediction studies. Here, using our ongoing large clinical cohort- Microbiome in aging Gut and Brain (MiaGB) consortium study, we plan to globally analyze proteomics and oral microbiome in saliva along with markers of inflammation in plasma of 60 cognitively normal, 60 MCI, and 40 dementia participants in both cross-sectional and prospective follow-up studies to test our hypotheses. We plan two specific aims. In Aim 1 we will determine if unique proteomic signatures differentiate subjects with MCI and dementia from cognitively healthy controls and if the addition of microbiome and inflammatory markers boosts the distinction; and in Aim 2, we will determine if saliva-based protein markers predict the risk of MCI and dementia progression and whether the inclusion of microbiome and inflammation strengthens the prediction in older adults. Building on an already ongoing large study and supported by compelling preliminary data and complementary expert team and interlinked aims, our study is expected to establish proof of concept that saliva-based biomarkers will diagnose an...