Project Summary 6.2 million Americans are living with Alzheimer’s disease (AD), experiencing reduced quality of life and irreversible deterioration of cognitive function. AD development is likely driven by inflammation in the central nervous system (CNS), yet there remain no broadly effective therapies. We propose that AD pathology may be, in part, caused by circadian dysregulation of peripheral immune cell migration through the CNS. The circadian clock is a critical regulator of biological processes, generating ~24 h rhythms in gene expression, hormone release, and behavior, but its efficacy in various cells and tissues deteriorates with age. Up to 70% of individuals with AD experience circadian disruption and sleep-wake disturbances, which often present years before clinical diagnosis. Circadian dysregulation is therefore a potential biomarker and signal for early intervention in age- and AD-related pathology. The immune system is tightly regulated by the circadian clock, generating daily cycles of immune cell migration throughout the body which leads to temporal windows of high and low immune reactivity. The immune system also critically regulates CNS function; peripheral inflammation disrupts behavior and impairs cognition. During aging, the CNS immune system gradually shifts from a balance between pro- and anti- inflammatory function towards a more reactive inflammatory state. Importantly, trafficking of adaptive immune cells to immune-brain interfaces regulates neuroinflammation and cognition. Thus, we hypothesize that circadian rhythms in immune cell trafficking to the CNS are disrupted with age and AD-like pathology, leading to cognitive and behavioral changes. This proposal addresses the following specific aims: First, establish the role of circadian dysregulation of immune cell trafficking in CNS inflammation and cognitive decline during aging and AD-like pathology; second, determine if disruption of molecular clocks in key brain-immune interface cells expedites cognitive decline during aging and AD-like pathology; and third, reveal whether reinstating daily trafficking rhythms via time-restricted feeding ameliorates age- and AD-induced pathology. This proposal is innovative in combining expertise in circadian biology, immunology, and behavioral neuroscience to understand how circadian regulation of brain barriers and immune cell trafficking through the CNS regulates aging and AD-like pathology. This contribution will be significant because our results will identify how circadian regulation of adaptive immune cell migration through the CNS affects local neuroimmune function. We expect that our results will identify a novel role for biological rhythms in regulating neuroinflammatory pathology and cognition via immune cell migration, highlighting novel therapeutic avenues to target cognitive decline and behavioral changes in aging, AD, and AD-related dementia.