Alzheimer’s disease (AD) is typically diagnosed by markers of amyloid-beta (ABeta) deposits in the brain, cerebrospinal fluid, and/or blood. So far, such hallmarks have proven insufficient for explaining the development of AD, and identifying at-risk individuals. A growing body of evidence suggests that ABeta is cleared via the glymphatic system, which is especially active during sleep, and it is now also thought that glymphatic function is driven by vascular pulsations. This is intriguing given the reliable findings of both vascular dysfunction and disordered sleep in AD patients, and together these observations suggest potential causal links between cerebrovascular status, sleep disruption, and AD progression. Indeed, reduced cerebrovascular pulsatility and changes in the blood pressure (BP) pulse wave have already shown to be related to AD severity. Currently, there is no technology suitable for long-duration (e.g. 24-hr) beat-to-beat characterization of these vascular and glymphatic dynamics in AD. If such monitoring was possible, this could help researchers investigate several extant hypotheses regarding the underlying mechanisms of AD, that ultimately could help to improve AD detection and treatment strategies. Our team at Massachusetts General Hospital has developed a wearable, multimodal cerebrovascular monitoring platform, called NINscan, which is capable of up to 24-hr use. This technology is being enhanced in our active R01 project (EB027122), using our novel superficial temporal artery tonometry (STAT) method for continuous, cuffless BP monitoring at the level of the head. This supplement proposes two specific aims. In Aim 1 we will further develop NINscan for multimodal cerebral vascular and fluid monitoring, as well as optimizing its use for ambulatory monitoring in AD. This will be accomplished by improving chromophore and depth sensitivity as well as patient usability. For Aim 2, we will conduct feasibility testing in older adults and AD patients, both in the lab and during 24-hr recordings (including daily activities and sleep). This data will allow us to conduct preliminary comparisons between healthy and patient groups on (i) BP, (ii) BP pulsatility, (iii) cerebral blood and water (glymphatic) volumes, and (iv) blood and water volume pulsatility. The data will also be added to the Physionet database being developed as part of EB027122. This supplement will lead to the most comprehensive cerebral monitoring system capable of 24-hr use, including static and dynamic BP and cerebral fluid measurements that appear key to AD. We expect that this enhanced capability will facilitate a better understanding of AD and hopefully stimulate the development of new diagnostics or therapies, as well as providing capabilities that are useful well beyond AD.