Preventing or delaying dementia and Alzheimer disease (AD) is a global priority. The gradual progression of the disease creates opportunities for both early detection and prevention. AD is complex and heterogeneous, and a combination of several easily available biomarkers that accurately reflect key pathologies is needed for early detection of people at-risk and matching the right individuals with the right interventions. Long-term studies with repeated biomarker measures across the entire disease continuum are lacking and no testing has been done in larger randomized controlled trials (RCTs). The landmark FINGER trial (Prof. Kivipelto is the PI) is the first and largest multimodal lifestyle-based RCT to show significant benefits in at risk older individuals, and has now expanded to global World-Wide FINGERS. Emerging technologies with high sensitivity and specificity for measuring AD and neurodegeneration related blood markers have led to recent observational studies showing very promising results for plasma Aβ42/40 ratio, phosphorylated (p)-tau181, p-tau231, neurofilament light chain (NFL, neurodegeneration marker), and glial fibrillary acidic protein (GFAP, early marker of Aβ-related reactive astrogliosis). We aim to clarify which of these novel blood markers (or their combinations) are most suitable for (i) reliably assessing the shorter- and longer-term efficacy of preventive interventions in modifying different AD-related pathological processes, (ii) matching the right people with the right interventions for optimal benefits, and (iii) providing tools for early detection of at risk/early disease stages. Importantly, we can study the relation between these new markers to other biomarkers, biological mechanisms, and clinical outcomes. The project will use repeated samples and data from FINGER (2-year intervention). A unique 11-year follow-up is included in the analyses. The project will provide first-time RCT-based evidence on AD blood biomarker framework and clarify the underlying mechanisms of the multidomain intervention. This is critical for developing novel therapeutic strategies for precision prevention trials.