PROJECT SUMMARY In order to accelerate observational clinical studies and trials and to identify appropriate patients for treatments, highly accurate and accessible diagnostic tests for Alzheimer's disease (AD) are needed. Clinical assessments alone are insufficient for accurate diagnoses, and the current gold standard tests for AD (CSF and PET) are costly, limited to specialized medical centers, and perceived to be invasive. In our ongoing prospective Study to Evaluate Amyloid in Blood and Imaging Related to Dementia (SEABIRD), we discovered that decreased blood plasma Aβ42/40 ratio is an accurate biomarker of amyloid plaques and confirmed this in a diverse community- based population, also demonstrating that blood tests are feasible to screen the general population. We have discovered and reported the most accurate Aβ42/40 and phosphorylated-tau blood biomarkers (%ptau217, %ptau205, and %ptau181) and discovered novel forms of neurofilament light (NfL) that promise to quantify the major domains of AD pathophysiology. With demonstration that removal of amyloid plaques leads to disease-modifying treatment clinical benefits, access to anti-amyloid therapies will depend on accurate diagnosis, and blood biomarkers will be critical tools for doctors and patients in underrepresented populations. However, there are multiple questions that need to be addressed to inform about the biology, use, and indications of these rapidly developing and utilized blood-based biomarkers. These questions include: `What are the diagnostic and prognostic properties of blood Aβ, tau, and neurodegeneration (A/T/N) biomarkers to measure amyloid and tau pathology, clinical cognitive decline, and diagnosis in a real-world clinical patient population?', and `Which demographic, clinical, or genetic factors influence the relationship of blood A/T/N biomarkers to the gold standards of clinical cognitive decline, dementia, and PET tests of pathology?' Our proposed study, called SUNBIRD (Study to Understand Novel Biomarkers in Researching Dementia), will enroll 1000 new participants from primary and specialty care clinics and follow the existing ~1000 SEABIRD participants. We will incorporate high performance blood-based biomarkers tracking amyloid, tau and neurodegeneration and assess their relationship with tau PET, amyloid PET, and other clinical AD tests. We will follow these cohorts longitudinally using blood samples, EHR data, and in-person and remote cognitive testing. We aim to understand how blood-based biomarkers can identify those with clinical symptoms due to AD pathology, determine if blood-based biomarkers can be utilized in lieu of PET or CSF measures, and also diagnose and stage patients to enable treatment and prevention in the clinic. The proposed work builds on the prior pioneering approach that discovered and validated blood amyloid biomarkers, discovered novel tau phosphorylation sites. These studies will lay the groundwork for rapid deployment to accelerate enr...