PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the most common form of dementia in older adults, has no known cure, and increasingly impacts society in terms of its human toll and healthcare costs. AD disproportionately affects women, even when accounting for women’s greater longevity and other sex-linked factors. This research focuses on the predominant sex hormones in older women and men (estradiol, estrone, testosterone) as protective factors against pre-clinical cognitive decline and mild cognitive impairment (MCI), which may be prodromal states of AD. Sex hormones reduce risk for AD and protect against cognitive decline in women and men and may do so through associations with reduced pro-inflammatory and increased anti-inflammatory signaling. Research rarely studies women and men concurrently and rarely examines the effects of ‘opposite- sex’ hormones (i.e., estrogens in men, testosterone in women) to compare the relative strength of sex hormones’ protective effects. Research on cognitive decline likewise has ignored age-related changes in estrone, the predominant estrogen in older women that may represent a separate protective pathway against cognitive decline. Moreover, studies linking sex hormones to cognitive decline lack rigorous assessments of inflammation as a pathway by which testosterone exerts its protective effects. This project investigates sex hormones’ (estradiol, estrone, and testosterone) influence on cognitive outcomes in adults aged 70+ years (n = 610) who are enrolled as part of the Einstein Aging Studies (EAS), an ongoing longitudinal cohort study. The EAS examines cognitive functioning via highly sensitive ambulatory assessments (6/day, 14 days/wave) across 3 annual waves, and via MCI prevalence at Wave 1. Blood collected before and after each assessment burst is assayed for a panel of pro- and anti-inflammatory cytokines, including basal circulating levels and stimulated responses. We propose to assay sex hormones from these same blood samples. We hypothesize that sex hormones will relate to better cognitive outcomes in Wave 1 in men and women, and that levels of pro- and anti-inflammatory biomarkers will partly mediate this effect. Similarly, we expect sex hormones will protect against cognitive decline and may do so via their effects on inflammation. This research broadens the impact of the ongoing, longitudinal EAS by linking sex hormones to sensitive measurement of cognitive states associated with AD. We will also examine sex hormones association with inflammatory load across the full two- week burst, and with individuals’ inflammatory responses in blood, which may be a more sensitive measure for the development of AD. The work is a necessary and timely investigation of sex hormones’ links to cognitive decline and MCI, which may be part of the long prodromal periods inherent to AD. Integrating this proposal into the EAS will provide a pipeline of new data that will inform and invigorate new research on the rou...