ABSTRACT – MIDUS OVERALL PLAN The Midlife in the U.S. (MIDUS) national longitudinal study has been ongoing since 1995. MIDUS is the only national study focused on midlife with a wide age expanse at baseline. MIDUS also has unusual depth in its psychosocial, biomarker, genomic, and neuroscience assessments, thus permitting a focus on neurobiological mechanisms and pathways through which sociodemographic and psychosocial factors influence morbidity and mortality. This application aims to conduct a 2nd wave of data collection on the MIDUS Refresher sample (MR2) as well as a 4th wave of data collection on the Core sample (M4), including all projects in both. Four projects (Survey, Daily Diary, Biomarkers, Genomics) are part of this U19 competing continuation application, which is linked with an Ancillary U01 application on Alzheimer’s Disease (AD) and Related Dementias (ADRD) that will examine midlife precursurs to cognitive decline, emotion regulation, brain aging, and their interplay. Much of that prior work is also longitudinal, although it now includes new ADRD neuroscience and biomarkers. Overall, the proposed activities involve over 5,200 U.S. adults that will be supported by an Administrative Core responsible for orchestrating cross-project data collection and delivering high-quality, well-documented data; a BioCore that ensures quality control in biomarker data collection and offers guidance on use of biomarkers; and a Statistics Core that provides workshops on multiple topics (modeling longitudinal change, using genomic data, linking MIDUS to other datasets). Recurring scientific themes in the proposed science are health inequalities and racial disparities examined with the rich biopsychosocial data available in MIDUS, including wide-ranging assessments of stress exposures across multiple waves, thereby providing indicators of cumulative adversity. MIDUS is also known for its comprehensive assessments of psychosocial and behavioral protective factors, thereby advancing research on resilience in the face of challenge. Aging on a changing historical stage is another key theme in MIDUS exemplified by a past focus on hardships of the Great Recession, and going forward, a new parallel focus on hardships of the COVID-19 pandemic. In terms of scientific engagement, MIDUS is the most frequently downloaded study at the National Archive of Computerized Data on Aging (NACDA). Widespread usage from the scientific community (26,000+ public users) has culminated in 1,617 publications covering 38 substantive domains. Underscoring the momentum behind MIDUS, more than half of these products are journal articles published during the current funding cycle (2016-present).