PROJECT SUMMARY/ABSTRACT Major depressive disorder (MDD) is a staggering public health challenge, manifesting in ~10% of adults in the US and contributing substantially to the global burden of disease and disability. Given the intimate reciprocal link between stress and MDD, a better understanding of the mechanisms underlying stress system dysfunction in MDD may provide clinically relevant insight into individually tailored preventive and therapeutic interventions. The goal of the parent grant is to rigorously interrogate the link between common everyday psychosocial stressors and sympathetic stress reactivity within multiple dimensions of behavior and physiology. Our central hypothesis is that the functional relation between daily stress processes (exposure and negative affective responsivity) and acute sympathetic stress reactivity [muscle sympathetic nerve activity (MSNA) responsiveness to acute laboratory-applied emotional and cognitive stressors] is sensitized and amplified in adults with MDD. This will represent a novel biosignature underlying stress system dysfunction in MDD, with profound implications for cardiovascular function and neurocognitive health. The purpose of this Alzheimer’s disease (AD)-focused Administrative Supplement is to expand the parent grant to also examine the effect of emotional responsiveness to daily memory lapses (e.g., forgetting someone’s name, misplacing car keys), a distinctive source of daily stress, on acute sympathetic stress reactivity in healthy non-depressed young-to-midlife adults (18-45 yrs) and in those with MDD. Daily memory lapses are a unique, typically overlooked, cause of daily stress that can activate stress-responsive neurocircuitry and elicit tangible affective and functional consequences. This emotional consequence of daily memory lapses is evident early in the aging trajectory (<40 yrs), well before the onset of detectable cognitive decline, but during the critical midlife period that has been identified as an opportune time for implementing lifestyle interventions that promote healthy neurocognitive aging. Our published and preliminary data suggest that negative affective responsivity to daily stress is heightened in adults with MDD and directly related to increased acute sympathetic stress reactivity. The central hypothesis of this AD-focused Administrative Supplement is that the positive relation between daily memory lapses and acute sympathetic stress reactivity is steeper in adults with MDD. Because excessive sympathetic outflow increases arterial stiffness, which is a key causative event in structural and functional abnormalities that accelerate neurocognitive decline, this exploratory project will provide initial insight into sympathetic stress reactivity as a potential physiological mechanism through which increased frequency of and negative affective responsivity to daily memory lapses increases AD risk and whether it is more pronounced in adults with MDD. Identifying this link ear...