Abstract In Alzheimer's disease (AD), tau accumulation begins in the perirhinal cortex (PC) and spreads to the entorhinal cortex (ERC) and hippocampus (regions in the Braak I-II stages). Although [18F]MK6240 is a promising PET radiotracer with a binding pattern that mirrors tau progression in AD, in vivo neuroimaging of the ERC/PC is hindered by the poor spatial resolution of PET and meningeal dura \spill-in" artifacts (also known as partial volume e ect or PVE). To address these challenges, we propose the development and clinical translation of our ultra-high resolution and upright Prism-PET brain scanner with integration of our ultra-high resolution electromagnetic motion tracker (EMMT). As new amyloid- targeting treatments for AD, such as lecanemab, become widely used, the need for PET scans may increase by a factor of 20, posing a major challenge for health systems to meet this demand, particularly outside of major metropolitan centers. In addition to having the highest spatial resolution, our Prism- PET/EMMT system is cost-e ective, upright, and portable and can be easily attached to CT scanners in the community, thereby increasing community access to brain PET imaging. We hypothesize that in Alzheimer's disease (AD), PET imaging of Braak I-II brain regions using [18F]MK6240 tau radiotracer and Prism-PET/EMMT scanner may be the earliest biomarker for detecting tau aggregation and AD severity in asymptomatic individuals. Given our promising preliminary experimental results, we aim to accomplish the following tasks: (Aim 1) Integration of Prism-PET with EMMT and conversion to upright position; (Aim 2) High resolution motion-compensated reconstruction (HRMR) followed by CT-based and CT-less attenuation correction; (Aim 3) Anthropomorphic phantom imaging and initial Tau-PET human validation; and nally (Aim 4) In vivo quantitative assessment of tau deposition in ERC/PC in amyloid-positive subjects with early mild cognitive impairment (MCI), using both supine and upright Prism-PET/EMMT scanning with the [18F]MK6240 tracer.

Narratives/Relevance We hypothesize that in Alzheimer's disease (AD), PET imaging of Braak I- II brain regions using [18F]MK6240 tau radiotracer and Prism-PET/EMMT scanner may be the earliest biomarker for detecting tau aggregation and AD severity in asymptomatic individuals.