PROJECT SUMMARY/ABSTRACT Pathogenesis and pathophysiology of AD and ADRD are multifaceted and complex. Varying individual factors further complicate the onset, progression and outcomes of the disease. For example, in spite of great interests and progress made in uncovering the association between cognitive decline and cardiovascular (CV) conditions, it largely remains unclear what other factors that are comorbid with CV conditions such as (neuro)inflammation, metabolic disorders and declined physical function, play a role and to what extent. With these often concurring conditions, it is challenging to disentangle independent or relative effects of those risk factors further confounded by individual differences. This RFA states one of the important topics as “… cardiovascular, metabolic and other risk factors; neuroinflammation; neuroimaging and other biomarkers…”, signifying the need for more comprehensive investigations on risk factor and marker identification to move the field forward and by engaging “new” workforce. Furthermore, it is paramount to pay more attention to identifying composite as well as independent risk for a cognitive decline by simultaneously investigating multi- system risk factors (“MRFs”) especially, among the high-risk individuals such as those with a cognitive function decline or mild cognitive impairment (MCI) or even those who are currently asymptomatic with identifiable risk factors in order to mobilize efforts in prevention of AD/ADRD. Thus, we propose to scrutinize multisystem risk factors categorized into following five domains in predicting cognitive function and impairment status: neuroinflammatory, metabolic, hemodynamic, psychosocial and physical functioning. Leveraging an ongoing R01 study of a behavioral intervention among elderly individuals (65 – 89 years of age) and recruiting additional participants (to include more individuals with a formal diagnosis of MCI using neuropsychological test) from Co-I, Dr. Delano-Woods’ clinic (UCSD Memory, Aging and Resilience Center, MARC), we will be able to utilize the existing and newly acquired data of proposed risk factors in five domains as well as cognitive outcomes. The cognitive function and impairment will be assessed and defined by using Montreal Cognitive Assessment (MoCA) and a neuropsychological (NP) battery for which the levels of ‘agreement’ between the two measures will be examined in the context of predictability of MRFs. The cross-sectional and prospective predictability of MRFs will be investigated and the sex and sex by age interaction effects will be tested.