Project HERA: Health and Environmental factors for Resilient Ageing in Adults Aged 60-75.

This project aims to determine the causal role of slow wave sleep on the clearance of amyloid and tau in a human model. It also aims to determine whether Alzheimer's Disease (AD) pathology and other individual factors impact the capacity to enhance slow wave sleep, and whether slow wave enhancement mediates improvement in clearance/cognition. Intervention (STIM): Acoustic stimulation of Slow wave sleep via phase-locked tones of pink noise Participants will monitor their sleep and activity patterns at home for one week using a wrist-worn actigraphy device and sleep diary for the full duration. On the last four nights of the week, participants will wear a Z-Max portable electroencephalography (EEG) headband (Hypnodyne) and a SleepPhones headband for four consecutive nights in their homes. The Z-Max headband will monitor and record their brain activity in real time, sending the data to a tablet, which will identify when the participant enters slow wave sleep, and administer 50ms tones of pink noise which will be played through the SleepPhones, timed with the up-phase of the slow wave. The tablet will run a custom algorithm to achieve slow wave prediction and timed administration of tones. Participants will be instructed to maintain an 8 hour sleep window each night of the monitoring period, and will be given an information booklet on how to run the procedure at home. After hours assistance from the trial coordinator will also be available to participants over the phone. Adherence to the intervention will be monitored by presence of timestamped data files at the end of each week. At the end of the week, participants will attend an in-person laboratory cognitive testing session for about 2.5 hours, wherein they will provide a small blood sample to assess the clearance of brain toxins. Their memory, processing speed, reaction time, alertness and language will also be assessed during these laboratory sessions by the research coordinator. A period of three nights with no intervention (washout) will separate the the stimulation week (STIM) from the control week (SHAM). The two weeks of the intervention trial are counterbalanced to control for order effects and habituation to wearing the equipment such that participants will be randomly allocated to complete either the STIM or the SHAM week first, balanced by sex. Following completion of both the STIM and SHAM weeks, participants will complete an overnight sleep laboratory visit for the assessment of slow wave sleep dynamics and overnight clearance of toxins. Prior to the assessment participants will complete 5 nights of sleep monitoring in their homes using a wrist-worn actigraphy monitor and sleep diary. Participants will then be admitted to the Austin Health Sleep Laboratory in the evening. Participants will be fitted with 20 channels of electroencephalography (EEG) for sleep monitoring, and have a cannula intravenously inserted in their forearm by a registered nurse. Participants will be infused with a heparin saline infusion to maintain hydration and cannula patency. A total of 5000 units of heparin sodium per litre of saline will be used across the night (a total of 2500 units). EEG will be recorded overnight, and blood samples will be collected every 30min throughout. Participants will be provided with an 8h sleep opportunity commencing at their habitual bedtime. Finally, participants will attend the Monash Biomedical Imaging facility and will be injected with 185 MBq of tau tracer 18F-PI2620 via intravenous cannula. Participants will undergo a 45min MR-PET scan after a 40min uptake time in order to assess tau pathology using Standardised Uptake Value Ratio (SUVR).