Twenty-four hour patterns of light and activity and Alzheimer's Disease and Related Dementia: interplay with multi-omics biomarkers and AD pathogenesis pathways - PROJECT SUMMARY Alzheimer's disease and related dementia (ADRD) is a highly debilitating syndrome and a major cause of morbidity, mortality and rising healthcare cost in the US. It is crucial to identify novel modifiable risk factors and deepen the understanding about biological mechanisms in ADRD etiology. This R01 renewal application is built upon the success of our existing R01 project, which showed that weakened rest-activity rhythms predicted higher ADRD risk and were associated with numerous metabolomics features, revealing key mechanisms underlying the adverse effects of circadian disruption. In this renewal application, we will leverage three well-documented cohorts, the Osteoporotic Fractures in Men (MrOS), Women's Health Initiative (WHI) and the UK Biobank and expand into three new directions: First, we will examine 24-hour light environment and its alignment with rest- activity rhythms as novel risk factors for ADRD. Second, we will identify biological mechanisms underlying circadian disruption and ADRD by integrating proteomics with metabolomics data. Third, by incorporating blood- and imaging-based biomarkers, we will explore potential differential associations of circadian disruption and omics features with ADRD across different ADRD pathological pathways. The new directions are directly supported by our preliminary data, and are operationalized into the following aims: Aim 1. Examine circadian rhythms (i.e., rest-activity rhythms, light exposure and their alignment) in relation to ADRD/cognition (i.e., ADRD risk (primary outcome), cognitive decline (secondary), and ADRD biomarkers (tertiary)). Hypothesis: Impaired circadian rhythms are associated with higher ADRD risk, more rapid cognitive decline, and altered ADRD biomarkers (Aim 1a), and the association between circadian rhythms and ADRD risk is modified by ADRD biomarkers (Aim 1b). Aim 2. Identify multi-omics features (integrated metabolomics-proteomics) associated with circadian rhythms and ADRD/cognition. Hypothesis: Numerous features are associated with rest-activity rhythms, light exposure and their alignment (Aim 2a). Multi-omics features are associated with ADRD risk, cognitive decline, and ADRD biomarkers, and the associations with ADRD risk are modified by ADRD biomarkers (Aim 2b). Aim 3. Determine the extent to which multi-omics features mediate the relationship between circadian rhythms and ADRD risk. Hypothesis: Multi-omics markers and pathways mediate the association of circadian rhythms with ADRD risk (Aim 3a), and the strength of mediation is modified ADRD biomarkers (Aim 3b). SIGNIFICANCE: Findings from our study will provide further evidence regarding the role of circadian disruption in ADRD and cognitive health in the aging population, strengthen the assessment of circadian function by including both behavioral and environmental data, identify novel biomarkers for disease etiology, and refine risk prediction. They may also motivate intervention strategies aimed at improving circadian function to reduce ADRD, and inform the development of digital biomarkers for risk prediction using wearable data.
