Sleep abnormalities have long been known to be a feature of neurodegenerative disorders and in some cases are considered a core manifestation of the disease. Patients with Alzheimer's disease exhibit disruptions of daily (circadian) sleep-wake rhythms, but it is unclear whether this reflects a primary disorder of internal circadian timekeeping and whether disruption contributes to symptoms and progression. It is largely assumed that disrupted sleep-wake rhythms are caused by the dampening of rhythms driven by the suprachiasmatic nucleus (SCN), a light-sensitive `master' circadian pacemaker responsible for synchronizing rhythms to the 24 h light-dark cycle. Alternatively, Alzheimer's pathology may be disrupting internal synchrony, between the SCN and other brain regions, organs, and tissues. To evaluate whether the internal synchrony of circadian rhythms is affected by Alzheimer's disease, we will measure the synchrony between standard and novel markers of circadian rhythms in (1) young healthy adults, (2) healthy elderly adults, and (3) patients with mild-moderate Alzheimer's disease. Together these aims will establish whether internal misalignment is a biomarker of Alzheimer's disease. Dr. Brianne Kent's strong background in research of circadian rhythms, cognition, and neurodegenerative disease provides her with the expertise to tackle this project. The K99 phase will provide her with essential training to study human circadian rhythms with a team of leading experts. She will be greatly assisted by her primary mentor Dr. Steven Lockley, who has extensive experience measuring circadian rhythmicity in humans under both laboratory and real-world conditions and is one of the few researchers examining internal synchrony. The Division of Sleep and Circadian Disorders at Brigham and Women's Hospital and Harvard Medical School have an exceptional training record and is the ideal program for continuing Dr. Kent's training. In addition to research training, the candidate has a detailed career development plan to enable her to build new skills and transition smoothly to an independent position, while ensuring time is adequately protected for research. Dr. Kent's goals are to (i) gain formal training in sleep and circadian neurobiological research in human subjects and (ii) gain further training in grant writing and professional development. Because of the innovative approach, timeliness, and importance, the proposed research plan should lead to important insights and publications. The in-depth scientific training and mentorship enabled by the K99/R00 will build upon Dr. Kent's existing expertise and will open many new research directions for her career as an independent researcher. The proposed project will grant Dr. Kent the necessary protected time to conduct research and to learn the requisite skills to achieve her long-term goals of launching an independent research program dedicated to understanding the neurobiology of Alzheimer's disease and developing novel therapeutics.
Alzheimer's disease is the most common cause of dementia, and unfortunately there are no effective treatments for this devastating disease. A promising target for new treatments is correcting for changes in the body's internal time-keeping mechanism - the circadian system. Here, we aim to identify the maladaptive changes in the circadian system associated with Alzheimer's disease, with the hope of identifying novel targets for therapeutics that will prevent the devastating memory loss associated with the disease, improve the quality of life of patients and their families, and reduce the economic burden of Alzheimer's disease.
