Project Summary/Abstract: Clinical trials targeting the reduction of amyloid-β and hyperphosphorylated tau load have been largely unsuccessful against neurodegenerative diseases including Alzheimer’s (AD) and AD-related dementias (ADRD). This may be due to the relatively late stage at which they are deployed, wherein cognitive symptoms are already manifest and the underlying inflammatory and degenerative processes are well underway. Conversely, prophylactic intervention aims to prevent or mitigate initiation of harmful, self-propagating disease processes before they become uncontrollable. For a treatment to be used prophylactically, ie before the presence of significant symptoms, it must be ‘trivially invasive’, simple to use, and inexpensive. This is critical for the expected benefits when deployed before symptoms to outweigh the potential risks. In this supplement, we propose a novel application of the minimally invasive InjectrodeTM technology outlined in the parent award to treat pain, to target brain waste clearance and cerebral hemodynamics through cranial nerve stimulation as a potential prophylactic strategy to combat AD. The Injectrode consists of a polymer matrix which is liquid in a syringe but quickly cures into a solid form when injected into the body. This technology offers many advantages over traditionally made electrodes amenable to prophylactic use including minimally invasive implantation (a simple injection). The successful completion of these aims would provide pilot data demonstrating the Injectrode concept can be utilized to improve the clearance of molecules within the brain, while identifying likely physiological components driving CSF/ISF interchange for future optimization.