Overall: Summary/Abstract The overall goal of ADNI is to validate biomarkers for AD clinical trials. ADNI data is widely used for planning AD trials and use of ADNI data has enabled dramatic changes to trial design, including early intervention strategies. ADNI data was used to design the aducanumab (Aduhlem™) trials leading to FDA approval. We have widely shared clinical/cognitive, imaging, and biomarker data and provided genetic, CSF, and plasma samples to the scientific community leading to over 3600 publications, providing major contributions to the overall knowledge of AD progression and pathophysiology. ADNI4 directly addresses two critical developments in field: incorporation of plasma biomarkers and enhancing recruitment of underrepresented populations (URPs). To address concerns about lack of generalizability, we created the Diversity Task Force which increased enrollment of URPs in ADNI3. This led to the creation of the Engagement Core which will focus on URP recruitment. Our goals are: first, to continue to validate biomarkers for AD clinical trials, and second, to recruit a more diverse participant population to create and share more generalizable data concerning the relationship of biomarkers and pathology to cognitive decline and dementia. This will be accomplished by: 1) Maintaining and widely sharing the digital data, biofluid, genetic and neuropathology repositories; 2) Following ~500 rollover participants from ADNI3, with priority for symptomatic and URP participants; 3) Greatly increasing recruitment of new URPs using a community-engaged approach employing “boots on the ground” recruiters, and navigators to provide digital/telephone support. Additionally, a digital marketing campaign targeted at URPs will screen and longitudinally assess 20,000 participants and identify 4000 (50-60% URPs) for blood collection at Quest Diagnostics phlebotomy centers. Plasma for A 42/40 and phospho-tau, will identify those AD biomarker+ (e.g., amyloid+). We will relax inclusion criteria to allow more comorbidities than in previous ADNI cohorts and thereby increase the prevalence of mixed dementias and cerebrovascular disease. This will facilitate enrollment of ~500 new participants (50-60% URPs, overall 80% amyloid +, 40% cognitively unimpaired, 40% MCI, 20% dementia) into the ADNI in-clinic battery (clinical assessment, MRI, PET, CSF, plasma). Thus, ~1000 participants will be enrolled into the in-clinic portion of ADNI4. The remaining 3500 participants will be followed longitudinally with follow-up blood testing. The MRI Core will add new sequences for cerebrovascular disease and improve harmonization. The PET Core will add new amyloid and tau PET tracers. Project 1 will optimize diagnosis of AD, monitoring change, and compare imaging and plasma biomarkers. In summary, we will recruit a diverse population for multisite clinical trials, demonstrating the feasibility of digital and blood test screening and monitoring participants on treatments. A...