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 ß42 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 ß42 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.