PROJECT SUMMARY / ABSTRACT In Alzheimer's disease (AD) research to mitigate the disease burden, there is a critical need to better utilize prospective cohorts. The need is especially great for population-based cohorts that include significant numbers of racial/ethnic minority individuals. In light of this, we initiated AD and related dementias (ADRD) research in the Multiethnic Cohort Study (MEC; 1993-current), the largest and most diverse cancer cohort in the US, composed at baseline of >215,000 adults of five ancestries (African, Japanese, Latino, Native Hawaiian, White) sampled in Hawaii and Southern California. We observed that the AD rates and the known risk factor associations in the MEC-Medicare linkage data are highly comparable to those reported in clinic-based studies, which assures the quality and generalizability of the MEC data for AD/ADRD research. We also found substantially higher AD risks and APOE e4 frequencies among Native Hawaiians as well as African Americans, compared to Whites. This and other important findings speak to the unique values of the MEC for AD/ADRD disparities research. However, one recurrent concern is that the AD/ADRD definitions in MEC are solely based on Medicare claims and, thus, may include misclassifications. Medicare claims-based disease outcomes are validated against clinical diagnosis. This approach is, however, less reliable for AD/ADRD because the current diagnostic gold standard, neuroimaging or cerebrospinal fluid biomarkers, is often inaccessible or intolerable, particularly to individuals of racial/ethnic minorities, rural residences and older ages, while clinical assessment without these biomarkers has known low accuracy. In this context, the blood-based maker (BBM) newly approved by FDA for initial screening of AD, phosphorylated tau-181 (pTau-181), provides a vital opportunity to robustly validate AD cases in MEC, while at the same time producing timely evaluation of the BBM by race/ethnicity. Thus, we propose to (Aim 1) replicate the association between plasma pTau-181 and ~570 incident AD cases using archived blood collected within 5 years of the first Medicare claim in a nested case- control study. We will evaluate the association overall and by sex, race/ethnicity and APOE e4. We will also (Aim 2) identify the determinants of plasma pTau-181 in AD cases, among the case-related, demographic (sex, race/ethnicity, age cohort, education, neighborhood socioeconomic status), genetic (APOE, polygenic risk score) and modifiable risk factor (vascular-metabolic disease history, physical activity, diet quality, sleep duration) characteristics available from the long-term, prospective follow-up, in order to understand the biomarker variation. The proposed work is within the scope of the active MEC grant (U01 CA164973; 2022-2027), as it will enhance the cohort infrastructure for investigations of genetic, lifestyle and environmental risk factors for an important chronic disease in US adults across mult...