The overall goal of Project 1 is to assess the roles of imaging and fluid biomarkers for detecting the presence of AD pathology, predicting disease progression, and monitoring disease progression within a diverse sample, with 50% - 60% of participants from underrepresented populations (e.g., Black, Latinx; persons from low resources settings). Participant selection with evidence of targeted pathological features, pathologic progression, and progression in clinical outcome measures are essential elements of AD clinical trial design. To develop an optimal and generalizable strategy for detecting AD pathology, and predicting and monitoring disease progression, it is important to compare the independent and added value of each class of biomarkers across all stages of the disease and in diverse cohorts. The goal of Project 1 is to determine the optimal combinations of plasma, CSF, and imaging biomarkers for cohort enrichment (phenotypical and prognostic features) that will minimize resource requirements and maximize power for clinical trials. This will provide a scalable and cost-effective approach for clinical trials to select participants who will benefit from treatment and to monitor longitudinal disease progression to determine treatment effects. Rich phenotypical data will be collected from: over 2500 participants enrolled in ADNI studies since 2004; 4000 participants to be enrolled in ADNI4 with plasma assays; 500 participants selected from the 4000 to be included in the ADNI4 longitudinal in-clinic biomarker and cognitive study; and 500 rollovers from ADNI3. Leveraging these data, we will determine the cross-sectional and longitudinal relationships between imaging and fluid measures of A, tau, neurodegeneration (AT(N)) and cerebrovascular disease (CVD) biomarkers that could be used to (1) select participants at different biomarker stages, and (2) determine the biomarker characteristics of disease progression. We will use advanced data harmonization, and disease progression modeling methods to (1) integrate diverse biomarker datasets, (2) examine patterns of pathology (A, tau, neurodegeneration, and CVD), and (3) construct biomarker signatures for the presence of AD pathology and the pathological and clinical disease progression. Our gold standards will be CSF and PET measures of Aβ and tau, and MRI measures of atrophy and CVD. We will achieve these goals by pursuing the following aims: Aim 1: Assess the value of imaging and fluid biomarkers in participant selection into clinical trials; Aim 2: Assess the longitudinal trajectories of imaging and fluid biomarkers as biomarker outcomes characteristic of disease progression; and Aim 3: Develop a trial enrichment simulation platform. Successful completion of Project 1 will provide a principled comprehensive platform, leveraging state-of-the-art biomarker analysis tools and strengths of ADNI Cores, to interpret multidisciplinary ADNI data in the context of AD clinical trials. We will provide a suit...