ABSTRACT MIDUS has unprecedented opportunities to advance knowledge of risk and protective factors for cognitive decline as well as for Alzheimer’s Disease (AD) and Related Dementias (ADRD). Such potential stems from its comprehensive assessments from two national samples (Core, Refresher) of behavioral, social, psychological, and biological assessments from prior decades in the participants’ lives. Identifying markers of risk before disease symptomatology is foremost to AD/ADRD prevention science. Key aims are to: (1) Conduct additional waves of cognitive assessments on both national samples and obtain new measures focused on cognitive impairment. The Brief Test of Adult Cognition will be re-administered to ~ 4,000 adults (Core n = 2,062; Refresher n = 1,935), ages 25 to 95 at the last wave with key neuropsychological assessments of memory, speed, fluency, reasoning, and executive functioning. Global cognitive status will be assessed with the Telephone Interview for Cognitive Status and self-reported symptoms. (2) Conduct additional waves of emotion-related functional neuroimaging and psychophysiological assessments on Core and Refresher Neuroscience subsamples and obtain comprehensive measures of brain aging. Multimodal neuroimaging and psychophysiological data will be collected on ~ 450 adults (Core n = 215 longitudinal + 60 new; Refresher n = 115 longitudinal + 60 new). Longitudinal analyses will examine changes in affective chronometry of emotional processes, computed brain age, atrophy, white matter structural integrity and hyperintensities, microstructural complexity of dendrites and axons, and network connectivity and modularity. (3) Quantify AD and neurovascular disease burden and collect new ADRD-related plasma and neuropsychological measures and clinical assessments in the Biomarker subsamples. Conduct advanced molecular amyloid PET to identify individuals exhibiting amyloid accumulation indicative of AD neuropathic change, and neurovascular MRI to identify vascular diseases including vessel stiffness and oligemic tissue perfusion. Cross-validate plasma markers of amyloid beta (42/40) against amyloid imaging in participants who have both, and in conjunction with the MIDUS U19 collect aβ42/aβ40, p-tau181, ptau217, total tau, and neurofilament light (NFL) on the full biomarker samples (~ 1280 participants; Core n = 630; Refresher n = 647), thereby extending the reach of MIDUS to include ADRD biomarkers. In conjunction with the U19 application, these new measures will be used to test hypotheses regarding cognitive decline and the precursors of AD/ADRD and neurovascular disease via cumulative stress over 30 years and consider socioeconomic and race disparities and resilience. The protective influence of biopsychosocial resources, affective style, and lifestyle factors assessed over multiple prior waves of MIDUS will be examined in relation to early indicators to gain a better understanding of the relations of these factors to cognitive imp...