PROJECT SUMMARY/ABSTRACT The rapid development of ultrasensitive immunoassays has made it possible to measure biomarkers for Alzheimer’s disease (AD) in blood with high accuracy, allowing for minimally invasive detection of disease pathology. A major advantage of using easily repeated measures of AD, as available with minimally invasive blood biomarkers, is the greater sensitivity and reliability for detecting within person change. In clinical trials this can dramatically reduce sample sizes needed to detect effect and potentially shorten the trial period by detecting treatment effects earlier. Collection of venous blood through phlebotomy is, however, still a medical procedure performed by trained staff requiring scheduled in-person visits in-clinic, or more rarely at-home, followed by sample processing in a timely manner. We will investigate and validate the use of dried blood spot (DBS) samples obtained through self-administered fingerstick, which can be collected at home by study participants themselves and be sent to the lab by mail, to measure blood-based biomarkers of AD. DBS has successfully been used to measure many analytes including a wide variety of proteins and peptides, but it is not established whether whole blood is a comparable matrix to plasma/serum for AD biomarker measurements and how stable DBS measurements of such biomarkers are over time. Our goals are to 1) optimize fingerstick collection methods for DBS samples and to perform fit-for-purpose validation of assays and parameters of measurement for pTau217, GFAP, and NfL, three key biomarkers reflecting AD pathology and neurodegeneration, in capillary DBS samples; 2) establish if DBS concentrations of the three biomarkers correlate with concentrations in paired plasma samples, and 3) evaluate the stability of measurements (precision) in repeated samples over a fourteen-week timeframe. The overarching goal of our study is to understand if frequent repeated measures of blood biomarkers in DBS samples can be incorporated as a sensitive measure for AD pathology in clinical trials of disease modifiers as well as in longitudinal and epidemiological observational research. The accessibility of DBS furthermore promises to increase diversity by being more inclusive, especially of ethnoracially, culturally, and geographically under-represented groups that traditionally experience more barriers to participate in clinical research.