PROJECT SUMMARY In this K23 career development award, Dr. Lawren VandeVrede, a behavioral neurologist and Assistant Professor at the University of California, San Francisco (UCSF), will obtain training in the use, validation, and translation of multimodal biomarkers for Alzheimer's Disease (AD) and related dementias (ADRD). This project supports his long-term career goal to become a leader in ADRD biomarker translation and novel clinical trial design, and to establish a lab that paves the way for a new generation of clinical trials that will evaluate and refine treatment approaches for patients with dementia. Through this K23 and the enriched multidisciplinary training environment at UCSF, Dr. VandeVrede aims to accomplish the following specific training goals: 1) gain expertise in the use of clinical, neuropathological, biofluid, and neuroimaging biomarker modalities, 2) develop specialized proficiency in validation of novel plasma AD biomarkers benchmarked to gold-standard neuropathology and current-generation positron emission tomography (PET) neuroimaging, and (3) develop a pathway for translation of biomarkers into clinical settings for use as large-scale screening and diagnostic tools for ADRD. To achieve these goals, Dr. VandeVrede has assembled an exemplary mentorship team, including his primary mentor, Dr. Adam Boxer, a leader in ADRD fluid biomarker discovery and clinical trial design, and co-mentors, Drs. Lea Grinberg and Gil Rabinovici, experts in ADRD neuropathology and PET imaging respectively. In addition, he has two collaborators with expertise in relevant plasma biomarker assays, Drs. Michelle Mielke and Jeff Dage, and a biostatistician, Dr. John Kornak, with significant expertise in ADRD biomarker validation and clinical trial design. The overarching goal of the project is to better characterize the diagnostic performance of several novel AD plasma biomarkers in an important and clinically relevant patient population: mixed etiology dementia. The central rationale is that blood tests are critically needed for large-scale diagnostic screening for AD, and whereas several proposed plasma biomarkers in the research world show promise as future clinical tools, key validation data and comparisons between biomarkers are missing in real-world dementia patients with mixed etiology. Therefore, in this project, novel plasma biomarkers of ADRD will be validated (1) in Aim I against gold-standard neuropathology in autopsy cohorts that include comorbid and alternative neuropathologies; (2) in Aim II against current-generation PET biomarkers in several prospective observational studies that include early, mixed, and atypical clinical phenotypes; and (3) in Aim III in a large community-based study specifically designed to recruit under-represented minorities. This project provides critical data that would support translation of these specific blood tests into clinical use, and establishes a platform for future discovery and validation project...