Responding to PAR 18-497: Sleep disorders and circadian clock disruption in Alzheimer?s disease and other dementias of aging, the overall goal of this study is to elucidate the brain molecular mechanisms underlying the bi-directional links between AD and sleep disruption in older adults. Sleep disruption predisposes to AD, while AD results in substantial sleep disruption. However, the brain molecular mechanisms underlying these bi-directional relationships remain obscure. Studies relating sleep disruption to the human transcriptome have generally involved adults without AD, examined blood rather than brain, and cannot distinguish sleep effects on AD from AD effects on sleep. We propose an innovative, cross-species translational approach to overcome these gaps. We will integrate transcriptome and proteome profiles from well-characterized human brains to identify promising gene associations with sleep fragmentation, AD pathology, and cognitive impairment, with validation of causal genes through which sleep fragmentation leads to AD pathology and cognitive impairment, and vice versa, based on genetic manipulation in Drosophila. In compelling pilot studies, we showed that sleep fragmentation in older humans is associated with a greater risk of incident AD. We have also defined a preliminary set of human genes that are significantly differentially expressed in prefrontal cortex in association with sleep fragmentation and both AD pathology and cognitive impairment. Moreover, from among these human candidate genes, we have successfully deployed ethologically relevant Drosophila paradigms to validate conserved genetic modifiers of sleep fragmentation, sleep-related cognitive plasticity, and both Tau and A? neurotoxicity. This study will collect new human lateral orbitofrontal cortex RNA sequencing data from 500 well-characterized older decedents from the Rush Memory and Aging Project (R01AG17911), integrate this with available proteomic data, and relate this to actigraphic sleep metrics, cognitive testing, and post-mortem indices of A? and Tau pathology to identify candidate brain- expressed genes underlying the bi-directional links between sleep fragmentation, AD pathology and cognition. To move beyond descriptive associations, we will use Drosophila genetics to validate causal roles for these genes in A?/Tau-induced neurodegeneration, cognitive plasticity, and sleep. Finally, leveraging available genomic data, we will confirm these causal relationships, observed in Drosophila, in humans using Mendelian randomization. Leveraging broad expertise, and augmenting human brain transcriptomics and proteomics with causal validation in Drosophila, this study will provide an in-depth description of the key bi-directional molecular mechanisms linking sleep fragmentation, AD pathology, and cognitive impairment. These genes will represent novel targets for further drug development to prevent the deleterious impact of sleep fragmentation on AD pathology and cognition, and to treat sleep fragmentation in adults with AD, with the potential to have a sustained impact on the health of millions of older Americans at risk for, or suffering from, AD.

RF1AG070436

2021-04-01

2024-03-31