Salivary Extracellular Vesicles as Biomarkers for Alzheimer's Disease and Related Disorders

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Project Summary: Alzheimer's disease (AD) and Related Disorders (ADRD), including frontotemporal dementia (FTD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), and amyotrophic lateral sclerosis (ALS), cause significant morbidity and mortality in aging populations. Despite decades of research, there are still no effective treatments to prevent or delay progression of these illnesses. Currently, there are tests available to identify individuals at risk of developing AD, but these tests require either a cerebral spinal fluid assay or positron emission tomography (PET) to measure amyloid levels, which are invasive or cost prohibitive, respectively, limiting their usefulness. While blood based diagnostic tests using amyloid and tau biomarkers are being developed to diagnose AD pathology in symptomatic individuals, their predictive value for preclinical disease is still unknown. Furthermore, there are currently no blood-based tests available for ADRDs. Since AD and ADRD develop over a prolonged period that can span decades, there is a need to identify individuals during this preclinical period when potential interventions may be more effective. To address our inability to diagnose at- risk individuals, we have put together a multidisciplinary team of investigators at Brown University and Rhode Island Hospital with the long-term goal to discover easily accessible biomarkers that can be used in a clinical setting to identify individuals at increased risk of developing AD or ADRD dementias prior to the onset of proteinopathies. Our group recently published that AD-related mRNA transcripts can be detected in extracellular vesicles (EVs) isolated from saliva in patients with traumatic brain injury. Our preliminary data show that patients with mild cognitive impairment (MCI) and mild AD have 43 mRNA transcripts and 5 miRNAs that show altered representation in salivary EVs. In addition, cognitively normal individuals with a PET scan that is positive for amyloid β42 have mRNA and miRNA profiles that are similar to the MCI and mild AD patients. Based on this data we hypothesize that the mRNA, miRNA, and protein composition of salivary EVs will provide valid biomarkers for early diagnosis and following disease progression in patients with AD and related neurodegenerative disorders. To test this hypothesis, we will use transcriptomic and proteomic approaches to define a set of RNA and protein biomarkers present in salivary EVs that predict an individual's risk of developing AD in Specific Aim 1. Specific Aim 2 will extend these investigations to identify RNA and protein biomarkers in salivary EVs isolated from individuals with FTD, PD, DLB, and ALS. In Specific Aim 3 we will determine the dynamics of changes in salivary EV composition during preclinical-to-AD clinical progression by following a cohort of cognitively normal individuals with positive amyloid β42 blood test over a period of 3-5 years. The data obtained in this project will allow us to identify biomarkers present in salivary EVs that can be used as a simple, noninvasive screening mechanism to detect patients at risk of developing AD during the preclinical phase when treatments may be more effective.